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1. Mitochondrial complex I deficiency stratifies idiopathic Parkinson’s disease

Author: Irene H. Flønes, Lilah Toker, Dagny Ann Sandnes, Martina Castelli, Sepideh Mostafavi, Njål Lura, Omnia Shadad, Erika Fernandez-Vizarra, Cèlia Painous, Alexandra Pérez-Soriano, Yaroslau Compta, Laura Molina-Porcel, Guido Alves, Ole-Bjørn Tysnes, Christian Dölle, Gonzalo S. Nido, and Charalampos Tzoulis
Subjects: Science
Abstract: Abstract Idiopathic Parkinson’s disease (iPD) is believed to have a heterogeneous pathophysiology, but molecular disease subtypes have not been identified. Here, we show that iPD can be stratified according to the severity of neuronal respiratory complex I (CI) deficiency, and identify two emerging disease subtypes with distinct molecular and clinical profiles. The CI deficient (CI-PD) subtype accounts for approximately a fourth of all cases, and is characterized by anatomically widespread neuronal CI deficiency, a distinct cell type-specific gene expression profile, increased load of neuronal mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes. In contrast, the non-CI deficient (nCI-PD) subtype exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and has a predilection for a tremor dominant phenotype. These findings constitute a step towards resolving the biological heterogeneity of iPD with implications for both mechanistic understanding and treatment strategies.
Published: 2024
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2. Residual Complex I activity and amphidirectional Complex II operation support glutamate catabolism through mtSLP in anoxia

Author: Dora Ravasz, David Bui, Sara Nazarian, Gergely Pallag, Noemi Karnok, Jennie Roberts, Bryan P. Marzullo, Daniel A. Tennant, Bennett Greenwood, Alex Kitayev, Collin Hill, Timea Komlódi, Carolina Doerrier, Kristyna Cunatova, Erika Fernandez-Vizarra, Erich Gnaiger, Michael A. Kiebish, Alexandra Raska, Krasimir Kolev, Bence Czumbel, Niven R. Narain, Thomas N. Seyfried, and Christos Chinopoulos
Subjects: Medicine, Science
Abstract: Abstract Anoxia halts oxidative phosphorylation (OXPHOS) causing an accumulation of reduced compounds in the mitochondrial matrix which impedes dehydrogenases. By simultaneously measuring oxygen concentration, NADH autofluorescence, mitochondrial membrane potential and ubiquinone reduction extent in isolated mitochondria in real-time, we demonstrate that Complex I utilized endogenous quinones to oxidize NADH under acute anoxia. 13C metabolic tracing or untargeted analysis of metabolites extracted during anoxia in the presence or absence of site-specific inhibitors of the electron transfer system showed that NAD+ regenerated by Complex I is reduced by the 2-oxoglutarate dehydrogenase Complex yielding succinyl-CoA supporting mitochondrial substrate-level phosphorylation (mtSLP), releasing succinate. Complex II operated amphidirectionally during the anoxic event, providing quinones to Complex I and reducing fumarate to succinate. Our results highlight the importance of quinone provision to Complex I oxidizing NADH maintaining glutamate catabolism and mtSLP in the absence of OXPHOS.
Published: 2024
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3. Measurement of mitochondrial respiratory chain enzymatic activities in Drosophila melanogaster samples

Author: Michele Brischigliaro, Elena Frigo, Erika Fernandez-Vizarra, Paolo Bernardi, and Carlo Viscomi
Subjects: Cell separation/fractionation, Metabolism, Model Organisms, Protein Biochemistry, Science (General), Q1-390
Abstract: Summary: Mitochondrial respiratory chain (MRC) dysfunction is linked to mitochondrial disease as well as other common conditions such as diabetes, neurodegeneration, cancer, and aging. Thus, the evaluation of MRC enzymatic activities is fundamental for diagnostics and research purposes on experimental models. Here, we provide a verified and reliable protocol for mitochondria isolation from various D. melanogaster samples and subsequent measurement of the activity of MRC complexes I–V plus citrate synthase (CS) through UV-VIS spectrophotometry.For complete details on the use and execution of this protocol, please refer to Brischigliaro et al. (2021).
Published: 2022
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4. Mitochondrial Neurodegeneration: Lessons from Drosophila melanogaster Models

Author: Michele Brischigliaro, Erika Fernandez-Vizarra, and Carlo Viscomi
Subjects: mitochondrial disease, neurodegeneration, OXPHOS, Drosophila melanogaster, Microbiology, QR1-502
Abstract: The fruit fly—i.e., Drosophila melanogaster—has proven to be a very useful model for the understanding of basic physiological processes, such as development or ageing. The availability of straightforward genetic tools that can be used to produce engineered individuals makes this model extremely interesting for the understanding of the mechanisms underlying genetic diseases in physiological models. Mitochondrial diseases are a group of yet-incurable genetic disorders characterized by the malfunction of the oxidative phosphorylation system (OXPHOS), which is the highly conserved energy transformation system present in mitochondria. The generation of D. melanogaster models of mitochondrial disease started relatively recently but has already provided relevant information about the molecular mechanisms and pathological consequences of mitochondrial dysfunction. Here, we provide an overview of such models and highlight the relevance of D. melanogaster as a model to study mitochondrial disorders.
Published: 2023
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5. Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila

Author: Simonetta Andreazza, Colby L. Samstag, Alvaro Sanchez-Martinez, Erika Fernandez-Vizarra, Aurora Gomez-Duran, Juliette J. Lee, Roberta Tufi, Michael J. Hipp, Elizabeth K. Schmidt, Thomas J. Nicholls, Payam A. Gammage, Patrick F. Chinnery, Michal Minczuk, Leo J. Pallanck, Scott R. Kennedy, and Alexander J. Whitworth
Subjects: Science
Abstract: The role of mitochondrial DNA mutations in organismal fitness and lifespan have been studied in mitochondrial mutator models with varying results. Here, the authors generate a new APOBEC1 expression-based Drosophila mutator model and show that it has limited mitochondrial function and reduced lifespan.
Published: 2019
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6. NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate

Author: Luigi D’Angelo, Elisa Astro, Monica De Luise, Ivana Kurelac, Nikkitha Umesh-Ganesh, Shujing Ding, Ian M. Fearnley, Giuseppe Gasparre, Massimo Zeviani, Anna Maria Porcelli, Erika Fernandez-Vizarra, and Luisa Iommarini
Subjects: respiratory complex I, CI, NDUFS3, CI modules, assembly factor, TMEM126A, Biology (General), QH301-705.5
Abstract: Summary: Complex I (CI) is the largest enzyme of the mitochondrial respiratory chain, and its defects are the main cause of mitochondrial disease. To understand the mechanisms regulating the extremely intricate biogenesis of this fundamental bioenergetic machine, we analyze the structural and functional consequences of the ablation of NDUFS3, a non-catalytic core subunit. We show that, in diverse mammalian cell types, a small amount of functional CI can still be detected in the complete absence of NDUFS3. In addition, we determine the dynamics of CI disassembly when the amount of NDUFS3 is gradually decreased. The process of degradation of the complex occurs in a hierarchical and modular fashion in which the ND4 module remains stable and bound to TMEM126A. We, thus, uncover the function of TMEM126A, the product of a disease gene causing recessive optic atrophy as a factor necessary for the correct assembly and function of CI.
Published: 2021
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7. Neural stem cells traffic functional mitochondria via extracellular vesicles.

Author: Luca Peruzzotti-Jametti, Joshua D Bernstock, Cory M Willis, Giulia Manferrari, Rebecca Rogall, Erika Fernandez-Vizarra, James C Williamson, Alice Braga, Aletta van den Bosch, Tommaso Leonardi, Grzegorz Krzak, Ágnes Kittel, Cristiane Benincá, Nunzio Vicario, Sisareuth Tan, Carlos Bastos, Iacopo Bicci, Nunzio Iraci, Jayden A Smith, Ben Peacock, Karin H Muller, Paul J Lehner, Edit Iren Buzas, Nuno Faria, Massimo Zeviani, Christian Frezza, Alain Brisson, Nicholas J Matheson, Carlo Viscomi, and Stefano Pluchino
Subjects: Biology (General), QH301-705.5
Abstract: Neural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs). EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids, and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs are yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics. Herein, we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells. Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs with conserved membrane potential and respiration. We found that the transfer of these mitochondria from EVs to mtDNA-deficient L929 Rho0 cells rescued mitochondrial function and increased Rho0 cell survival. Furthermore, the incorporation of mitochondria from EVs into inflammatory mononuclear phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits. Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases.
Published: 2021
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8. A homozygous MRPL24 mutation causes a complex movement disorder and affects the mitoribosome assembly

Author: Michela Di Nottia, Maria Marchese, Daniela Verrigni, Christian Daniel Mutti, Alessandra Torraco, Romina Oliva, Erika Fernandez-Vizarra, Federica Morani, Giulia Trani, Teresa Rizza, Daniele Ghezzi, Anna Ardissone, Claudia Nesti, Gessica Vasco, Massimo Zeviani, Michal Minczuk, Enrico Bertini, Filippo Maria Santorelli, and Rosalba Carrozzo
Subjects: Mitochondrial disorders, Movement disorder, MRPL24, Mitoribosomes, Mitochondrial protein synthesis, Zebrafish, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Mitochondrial ribosomal protein large 24 (MRPL24) is 1 of the 82 protein components of mitochondrial ribosomes, playing an essential role in the mitochondrial translation process.We report here on a baby girl with cerebellar atrophy, choreoathetosis of limbs and face, intellectual disability and a combined defect of complexes I and IV in muscle biopsy, caused by a homozygous missense mutation identified in MRPL24. The variant predicts a Leu91Pro substitution at an evolutionarily conserved site. Using human mutant cells and the zebrafish model, we demonstrated the pathological role of the identified variant. In fact, in fibroblasts we observed a significant reduction of MRPL24 protein and of mitochondrial respiratory chain complex I and IV subunits, as well a markedly reduced synthesis of the mtDNA-encoded peptides. In zebrafish we demonstrated that the orthologue gene is expressed in metabolically active tissues, and that gene knockdown induced locomotion impairment, structural defects and low ATP production. The motor phenotype was complemented by human WT but not mutant cRNA. Moreover, sucrose density gradient fractionation showed perturbed assembly of large subunit mitoribosomal proteins, suggesting that the mutation leads to a conformational change in MRPL24, which is expected to cause an aberrant interaction of the protein with other components of the 39S mitoribosomal subunit.
Published: 2020
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9. MR-1S Interacts with PET100 and PET117 in Module-Based Assembly of Human Cytochrome c Oxidase

Author: Sara Vidoni, Michael E. Harbour, Sergio Guerrero-Castillo, Alba Signes, Shujing Ding, Ian M. Fearnley, Robert W. Taylor, Valeria Tiranti, Susanne Arnold, Erika Fernandez-Vizarra, and Massimo Zeviani
Subjects: cytochrome c oxidase, mitochondrial respiratory chain, COX assembly, PET100, PET117, myofibrillogenesis regulator 1 short isoform, MR-1S, complexome profiling, SILAC, Biology (General), QH301-705.5
Abstract: The biogenesis of human cytochrome c oxidase (COX) is an intricate process in which three mitochondrial DNA (mtDNA)-encoded core subunits are assembled in a coordinated way with at least 11 nucleus-encoded subunits. Many chaperones shared between yeast and humans are involved in COX assembly. Here, we have used a MT-CO3 mutant cybrid cell line to define the composition of assembly intermediates and identify new human COX assembly factors. Quantitative mass spectrometry analysis led us to modify the assembly model from a sequential pathway to a module-based process. Each module contains one of the three core subunits, together with different ancillary components, including HIGD1A. By the same analysis, we identified the short isoform of the myofibrillogenesis regulator 1 (MR-1S) as a new COX assembly factor, which works with the highly conserved PET100 and PET117 chaperones to assist COX biogenesis in higher eukaryotes.
Published: 2017
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10. Knockdown of APOPT1/COA8 Causes Cytochrome c Oxidase Deficiency, Neuromuscular Impairment, and Reduced Resistance to Oxidative Stress in Drosophila melanogaster

Author: Michele Brischigliaro, Samantha Corrà, Claudia Tregnago, Erika Fernandez-Vizarra, Massimo Zeviani, Rodolfo Costa, and Cristiano De Pittà
Subjects: APOPT1, Drosophila melanogaster, cytochrome c oxidase deficiency, mitochondrial disease, resistance to oxidative stress, knockdown models, Physiology, QP1-981
Abstract: Cytochrome c oxidase (COX) deficiency is the biochemical hallmark of several mitochondrial disorders, including subjects affected by mutations in apoptogenic-1 (APOPT1), recently renamed as COA8 (HGNC:20492). Loss-of-function mutations are responsible for a specific infantile or childhood-onset mitochondrial leukoencephalopathy with a chronic clinical course. Patients deficient in COA8 show specific COX deficiency with distinctive neuroimaging features, i.e., cavitating leukodystrophy. In human cells, COA8 is rapidly degraded by the ubiquitin-proteasome system, but oxidative stress stabilizes the protein, which is then involved in COX assembly, possibly by protecting the complex from oxidative damage. However, its precise function remains unknown. The CG14806 gene (dCOA8) is the Drosophila melanogaster ortholog of human COA8 encoding a highly conserved COA8 protein. We report that dCOA8 knockdown (KD) flies show locomotor defects, and other signs of neurological impairment, reduced COX enzymatic activity, and reduced lifespan under oxidative stress conditions. Our data indicate that KD of dCOA8 in Drosophila phenocopies several features of the human disease, thus being a suitable model to characterize the molecular function/s of this protein in vivo and the pathogenic mechanisms associated with its defects.
Published: 2019
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11. APOPT1/COA8 assists COX assembly and is oppositely regulated by UPS and ROS

Author: Alba Signes, Raffaele Cerutti, Anna S Dickson, Cristiane Benincá, Elizabeth C Hinchy, Daniele Ghezzi, Rosalba Carrozzo, Enrico Bertini, Michael P Murphy, James A Nathan, Carlo Viscomi, Erika Fernandez‐Vizarra, and Massimo Zeviani
Subjects: APOPT1‐COA8, cytochrome c oxidase, mitochondrial encephalopathy, proteasome–ubiquitin system, reactive oxygen species, Medicine (General), R5-920, Genetics, QH426-470
Abstract: Abstract Loss‐of‐function mutations in APOPT1, a gene exclusively found in higher eukaryotes, cause a characteristic type of cavitating leukoencephalopathy associated with mitochondrial cytochrome c oxidase (COX) deficiency. Although the genetic association of APOPT1 pathogenic variants with isolated COX defects is now clear, the biochemical link between APOPT1 function and COX has remained elusive. We investigated the molecular role of APOPT1 using different approaches. First, we generated an Apopt1 knockout mouse model which shows impaired motor skills, e.g., decreased motor coordination and endurance, associated with reduced COX activity and levels in multiple tissues. In addition, by achieving stable expression of wild‐type APOPT1 in control and patient‐derived cultured cells we ruled out a role of this protein in apoptosis and established instead that this protein is necessary for proper COX assembly and function. On the other hand, APOPT1 steady‐state levels were shown to be controlled by the ubiquitination–proteasome system (UPS). Conversely, in conditions of increased oxidative stress, APOPT1 is stabilized, increasing its mature intramitochondrial form and thereby protecting COX from oxidatively induced degradation.
Published: 2019
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12. How do human cells react to the absence of mitochondrial DNA?

Author: Rossana Mineri, Norman Pavelka, Erika Fernandez-Vizarra, Paola Ricciardi-Castagnoli, Massimo Zeviani, and Valeria Tiranti
Subjects: Medicine, Science
Abstract: Mitochondrial biogenesis is under the control of two different genetic systems: the nuclear genome (nDNA) and the mitochondrial genome (mtDNA). The mtDNA is a circular genome of 16.6 kb encoding 13 of the approximately 90 subunits that form the respiratory chain, the remaining ones being encoded by the nDNA. Eukaryotic cells are able to monitor and respond to changes in mitochondrial function through alterations in nuclear gene expression, a phenomenon first defined in yeast and known as retrograde regulation. To investigate how the cellular transcriptome is modified in response to the absence of mtDNA, we used Affymetrix HG-U133A GeneChip arrays to study the gene expression profile of two human cell lines, 143BTK(-) and A549, which had been entirely depleted of mtDNA (rho(o) cells), and compared it with that of corresponding undepleted parental cells (rho(+) cells).Our data indicate that absence of mtDNA is associated with: i) a down-regulation of cell cycle control genes and a reduction of cell replication rate, ii) a down-regulation of nuclear-encoded subunits of complex III of the respiratory chain and iii) a down-regulation of a gene described as the human homolog of ELAC2 of E. coli, which encodes a protein that we show to also target to the mitochondrial compartment.Our results indicate a strong correlation between mitochondrial biogenesis and cell cycle control and suggest that some proteins could have a double role: for instance in controlling both cell cycle progression and mitochondrial functions. In addition, the finding that ELAC2 and maybe other transcripts that are located into mitochondria, are down-regulated in rho(o) cells, make them good candidates for human disorders associated with defective replication and expression of mtDNA.
Published: 2009
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13. Mitochondrial translation is the primary determinant of secondary mitochondrial complex I deficiencies

Author: Kristýna Čunátová, Marek Vrbacký, Guillermo Puertas-Frias, Lukáš Alán, Marie Vanišová, María José Saucedo-Rodríguez, Josef Houštěk, Erika Fernández-Vizarra, Jiří Neužil, Alena Pecinová, Petr Pecina, and Tomáš Mráček
Subjects: Biochemistry, Molecular biology, Cell biology, Science
Abstract: Summary: Individual complexes of the mitochondrial oxidative phosphorylation system (OXPHOS) are not linked solely by their function; they also share dependencies at the maintenance/assembly level, where one complex depends on the presence of a different individual complex. Despite the relevance of this “interdependence” behavior for mitochondrial diseases, its true nature remains elusive. To understand the mechanism that can explain this phenomenon, we examined the consequences of the aberration of different OXPHOS complexes in human cells. We demonstrate here that the complete disruption of each of the OXPHOS complexes resulted in a decrease in the complex I (cI) level and that the major reason for this is linked to the downregulation of mitochondrial ribosomal proteins. We conclude that the secondary cI defect is due to mitochondrial protein synthesis attenuation, while the responsible signaling pathways could differ based on the origin of the OXPHOS defect.
Published: 2024
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14. Cooperative assembly of the mitochondrial respiratory chain

Author: Cristina Ugalde and Erika Fernandez-Vizarra
Subjects: Electron Transport, Mammals, assembly factors, mitochondria, supercomplexes, Mitochondrial Membranes, cooperative assembly model, plasticity model, respiratory chain organization, Animals, Molecular Biology, Biochemistry
Abstract: Deep understanding of the pathophysiological role of the mitochondrial respiratory chain (MRC) relies on a well-grounded model explaining how its biogenesis is regulated. The lack of a consistent framework to clarify the modes and mechanisms governing the assembly of the MRC complexes and supercomplexes (SCs) works against progress in the field. The plasticity model was postulated as an attempt to explain the coexistence of mammalian MRC complexes as individual entities and associated in SC species. However, mounting data accumulated throughout the years question the universal validity of the plasticity model as originally proposed. Instead, as we argue here, a cooperative assembly model provides a much better explanation to the phenomena observed when studying MRC biogenesis in physiological and pathological settings.
Published: 2022

15. Loss of COX4I1 leads to combined respiratory chain deficiency and impaired mitochondrial protein synthesis

Author: Tomáš Mráček, Erika Fernandez-Vizarra, Shujing Ding, David Pajuelo Reguera, Marek Vrbacký, Josef Houštěk, Ian M. Fearnley, Kristýna Čunátová, Petr Pecina, Massimo Zeviani, Zeviani, Massimo [0000-0002-9067-5508], Houštěk, Josef [0000-0002-8413-4772], Pecina, Petr [0000-0003-0641-2834], and Apollo - University of Cambridge Repository
Subjects: Mitochondrial DNA, cIV, Mitochondrial Diseases, Protein subunit, Oxidative phosphorylation, cI, Mitochondrion, cIV assembly, Article, Oxidative Phosphorylation, Electron Transport Complex IV, Mitochondrial Proteins, Oxygen Consumption, mitochondrial protein synthesis, Cytochrome c oxidase, Humans, Inner mitochondrial membrane, biogenesis interdependency, lcsh:QH301-705.5, COX4, knock-out, biology, Chemistry, complex I, complexome profiling, COX, General Medicine, OXPHOS, mitochondria, Glycolysis, HEK293 Cells, Protein Subunits, Protein Biosynthesis, Cell biology, COX4I1, lcsh:Biology (General), Coenzyme Q – cytochrome c reductase, biology.protein
Abstract: Funder: Akademie Věd České Republiky; Grant(s): RVO:67985823, The oxidative phosphorylation (OXPHOS) system localized in the inner mitochondrial membrane secures production of the majority of ATP in mammalian organisms. Individual OXPHOS complexes form supramolecular assemblies termed supercomplexes. The complexes are linked not only by their function but also by interdependency of individual complex biogenesis or maintenance. For instance, cytochrome c oxidase (cIV) or cytochrome bc1 complex (cIII) deficiencies affect the level of fully assembled NADH dehydrogenase (cI) in monomeric as well as supercomplex forms. It was hypothesized that cI is affected at the level of enzyme assembly as well as at the level of cI stability and maintenance. However, the true nature of interdependency between cI and cIV is not fully understood yet. We used a HEK293 cellular model where the COX4 subunit was completely knocked out, serving as an ideal system to study interdependency of cI and cIV, as early phases of cIV assembly process were disrupted. Total absence of cIV was accompanied by profound deficiency of cI, documented by decrease in the levels of cI subunits and significantly reduced amount of assembled cI. Supercomplexes assembled from cI, cIII, and cIV were missing in COX4I1 knock-out (KO) due to loss of cIV and decrease in cI amount. Pulse-chase metabolic labeling of mitochondrial DNA (mtDNA)-encoded proteins uncovered a decrease in the translation of cIV and cI subunits. Moreover, partial impairment of mitochondrial protein synthesis correlated with decreased content of mitochondrial ribosomal proteins. In addition, complexome profiling revealed accumulation of cI assembly intermediates, indicating that cI biogenesis, rather than stability, was affected. We propose that attenuation of mitochondrial protein synthesis caused by cIV deficiency represents one of the mechanisms, which may impair biogenesis of cI.
Published: 2021

16. CEDAR, an online resource for the reporting and exploration of complexome profiling data

Author: Petra Páleníková, Jyoti S. Choudhary, Cristina Ugalde, Ulrich Brandt, Lars Wöhlbrand, Susanne Arnold, Sergio Guerrero-Castillo, Felix Evers, Joeri van Strien, Martijn A. Huynen, Uwe Schulte, Alexander Haupt, Taco W. A. Kooij, Hans-Peter Braun, Alfredo Cabrera-Orefice, Erika Fernandez-Vizarra, Ilka Wittig, and Mercedes Pardo
Subjects: Dewey Decimal Classification::500 | Naturwissenschaften::570 | Biowissenschaften, Biologie, Databases, Factual, Proteome, Computer science, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], protein fingerprinting, Proteomics, computer.software_genre, Biochemistry, 0302 clinical medicine, Resource (project management), online system, data base, Profiling (information science), Native protein, data visualization, multiprotein complex, FAIR, mass spectrometry, 0303 health sciences, Database, quantitative analysis, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], dynamics, omics, priority journal, factual database, User interface, Complexome profiling, Biophysics, Fractionation, Mass spectrometry, Article, Databases, 03 medical and health sciences, Data visualization, All institutes and research themes of the Radboud University Medical Center, proteomics, ddc:570, Humans, fractionation, human, Factual, 030304 developmental biology, complexome profiling data resource, Profiling (computer programming), business.industry, software, Protein complex, Multiprotein Complexes, Proteins, Software, Cell Biology, Omics, business, protein, computer, metabolism, 030217 neurology & neurosurgery
Abstract: Complexome profiling is an emerging ‘omics approach that systematically interrogates the composition of protein complexes (the complexome) of a sample, by combining biochemical separation of native protein complexes with mass-spectrometry based quantitation proteomics. The resulting fractionation profiles hold comprehensive information on the abundance and composition of the complexome, and have a high potential for reuse by experimental and computational researchers. However, the lack of a central resource that provides access to these data, reported with adequate descriptions and an analysis tool, has limited their reuse. Therefore, we established the ComplexomE profiling DAta Resource (CEDAR, www3.cmbi.umcn.nl/cedar/), an openly accessible database for depositing and exploring mass spectrometry data from complexome profiling studies. Compatibility and reusability of the data is ensured by a standardized data and reporting format containing the “minimum information required for a complexome profiling experiment” (MIACE). The data can be accessed through a user-friendly web interface, as well as programmatically using the REST API portal. Additionally, all complexome profiles available on CEDAR can be inspected directly on the website with the profile viewer tool that allows the detection of correlated profiles and inference of potential complexes. In conclusion, CEDAR is a unique, growing and invaluable resource for the study of protein complex composition and dynamics across biological systems.
Published: 2021

17. Mitochondrial disorders of the OXPHOS system

Author: Massimo Zeviani and Erika Fernandez-Vizarra
Subjects: biogenesis of the respiratory chain, Mitochondrial Diseases, Cellular respiration, Mitochondrial disease, Biophysics, oxidative phosphorylation, mitochondrial respiratory chain, Oxidative phosphorylation, mitochondrial proton pumping, DNA, Mitochondrial, Biochemistry, Electron Transport, 03 medical and health sciences, Adenosine Triphosphate, Structural Biology, ATP production, Mitochondrial respiratory chain, mitochondrial disease, mitochondrial electrochemical gradient, mitochondrial potential, respiratory complex, respiratory supercomplex, Genetics, medicine, Animals, Humans, Electron Transport Chain Complex Proteins, Mitochondria, Molecular Biology, 030304 developmental biology, 0303 health sciences, ATP synthase, biology, Chemiosmosis, Chemistry, 030302 biochemistry & molecular biology, Cell Biology, DNA, medicine.disease, Electron transport chain, Cell biology, Mitochondrial, biology.protein, Biogenesis
Abstract: Mitochondrial disorders are among the most frequent inborn errors of metabolism, their primary cause being the dysfunction of the oxidative phosphorylation system (OXPHOS). OXPHOS is composed of the electron transport chain (ETC), formed by four multimeric enzymes and two mobile electron carriers, plus an ATP synthase [also called complex V (cV)]. The ETC performs the redox reactions involved in cellular respiration while generating the proton motive force used by cV to synthesize ATP. OXPHOS biogenesis involves multiple steps, starting from the expression of genes encoded in physically separated genomes, namely the mitochondrial and nuclear DNA, to the coordinated assembly of components and cofactors building each individual complex and eventually the supercomplexes. The genetic cause underlying around half of the diagnosed mitochondrial disease cases is currently known. Many of these cases result from pathogenic variants in genes encoding structural subunits or additional factors directly involved in the assembly of the ETC complexes. Here, we review the historical and most recent findings concerning the clinical phenotypes and the molecular pathological mechanisms underlying this particular group of disorders.
Published: 2021

18. Neural stem cells traffic functional mitochondria via extracellular vesicles

Author: Erika Fernandez-Vizarra, Carlo Viscomi, Ágnes Kittel, Sisareuth Tan, Christian Frezza, Stefano Pluchino, Cristiane Benincá, Nunzio Vicario, Massimo Zeviani, Tommaso Leonardi, Ben Peacock, Paul J. Lehner, Alice Braga, Joshua D. Bernstock, Aletta Van Den Bosch, Jayden A. Smith, Karin H. Muller, Carlos Bastos, Edit I. Buzás, Luca Peruzzotti-Jametti, Giulia Manferrari, Cory M. Willis, Alain Brisson, Nunzio Iraci, Rebecca Rogall, Nuno Faria, Grzegorz Krzak, James C Williamson, Nicholas J Matheson, Iacopo Bicci, Chimie et Biologie des Membranes et des Nanoobjets (CBMN), École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), European Project: 258803, Peruzzotti-Jametti, Luca [0000-0002-9396-5607], Bernstock, Joshua D [0000-0002-7814-3867], Willis, Cory M [0000-0001-7938-7276], Manferrari, Giulia [0000-0001-7062-1142], Rogall, Rebecca [0000-0003-0605-2322], Fernandez-Vizarra, Erika [0000-0002-2469-142X], Williamson, James C [0000-0002-2009-189X], Braga, Alice [0000-0003-3273-9742], van den Bosch, Aletta [0000-0001-8886-8928], Leonardi, Tommaso [0000-0002-4449-1863], Benincá, Cristiane [0000-0001-7933-860X], Vicario, Nunzio [0000-0001-5934-3962], Tan, Sisareuth [0000-0003-3633-6318], Bicci, Iacopo [0000-0001-6994-3857], Iraci, Nunzio [0000-0003-2146-9329], Smith, Jayden A [0000-0003-2307-8452], Peacock, Ben [0000-0002-7823-8719], Muller, Karin H [0000-0003-4693-8558], Brisson, Alain [0000-0003-0342-352X], Matheson, Nicholas J [0000-0002-3318-1851], Apollo - University of Cambridge Repository, Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Bernstock, Joshua D. [0000-0002-7814-3867], Willis, Cory M. [0000-0001-7938-7276], Williamson, James C. [0000-0002-2009-189X], Smith, Jayden A. [0000-0003-2307-8452], Muller, Karin H. [0000-0003-4693-8558], and Matheson, Nicholas J. [0000-0002-3318-1851]
Subjects: 0301 basic medicine, Central Nervous System, Proteomics, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Cell Membranes, Artificial Gene Amplification and Extension, Mitochondrion, Outer membrane proteins, Inbred C57BL, Exosomes, Biochemistry, Nervous System, Transgenic, White Blood Cells, Database and Informatics Methods, Mice, 0302 clinical medicine, Neural Stem Cells, Animal Cells, Medicine and Health Sciences, Computer software, Biology (General), Energy-Producing Organelles, Cells, Cultured, Phagocytes, Cultured, Proteomic Databases, General Neuroscience, Neural stem cell, Cell biology, Mitochondria, Polymerase chain reaction, medicine.anatomical_structure, Female, Stem cell, Cellular Structures and Organelles, Cellular Types, Anatomy, General Agricultural and Biological Sciences, Research Article, QH301-705.5, Cells, Immune Cells, Central nervous system, Immunology, Green Fluorescent Proteins, Mice, Transgenic, Biology, Bioenergetics, Research and Analysis Methods, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Extracellular Vesicles, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Organelle, medicine, Animals, Vesicles, Molecular Biology Techniques, Molecular Biology, Blood Cells, General Immunology and Microbiology, Biology and Life Sciences, Membrane Proteins, Biological Transport, Mesenchymal Stem Cells, Cell Biology, Microvesicles, Transplantation, Mice, Inbred C57BL, 030104 developmental biology, Biological Databases, 030217 neurology & neurosurgery
Abstract: Neural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs). EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids, and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs are yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics. Herein, we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells. Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs with conserved membrane potential and respiration. We found that the transfer of these mitochondria from EVs to mtDNA-deficient L929 Rho0 cells rescued mitochondrial function and increased Rho0 cell survival. Furthermore, the incorporation of mitochondria from EVs into inflammatory mononuclear phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits. Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases., This study shows that neural stem cells are able to transfer functional mitochondria via extracellular vesicles to target cells both in vitro and in vivo, suggesting that functional mitochondrial transfer via extracellular vesicles is a signaling mechanism used by neural stem cells to modulate the physiology and metabolism of target cells.
Published: 2021

19. NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate

Author: Anna Maria Porcelli, Giuseppe Gasparre, Ivana Kurelac, Erika Fernandez-Vizarra, Luigi D'Angelo, Shujing Ding, Nikkitha Umesh-Ganesh, Monica De Luise, Massimo Zeviani, Elisa Astro, Luisa Iommarini, Ian M. Fearnley, D’Angelo, Luigi, Astro, Elisa, De Luise, Monica, Kurelac, Ivana, Umesh-Ganesh, Nikkitha, Ding, Shujing, Fearnley, Ian M., Gasparre, Giuseppe, Zeviani, Massimo, Porcelli, Anna Maria, Fernandez-Vizarra, Erika, and Iommarini, Luisa
Subjects: Models, Molecular, Proteomics, 0301 basic medicine, Bioenergetics, Protein Conformation, NDUFS3, SILAC, Gene Knockout Techniques, Mice, 0302 clinical medicine, Models, Stable isotope labeling by amino acids in cell culture, Biology (General), Gene Editing, Disease gene, Tumor, Chemistry, CI, optic atrophy type 7, respiratory complex I CI NDUFS3 CI modules assembly factor TMEM126A SILAC optic atrophy type 7, Mitochondria, Cell biology, CI modules, TMEM126A, assembly factor, respiratory complex I, Animals, Binding Sites, CRISPR-Cas Systems, Cell Line, Tumor, Electron Transport Complex I, Gene Expression Regulation, HCT116 Cells, Humans, Melanocytes, Membrane Proteins, Mitochondrial Membranes, NADH Dehydrogenase, Optic Atrophy, Osteoblasts, Protein Binding, Mitochondrial respiratory chain, QH301-705.5, Protein subunit, Mitochondrial disease, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, medicine, Molecular, medicine.disease, 030104 developmental biology, 030217 neurology & neurosurgery, Function (biology), Biogenesis
Abstract: Summary Complex I (CI) is the largest enzyme of the mitochondrial respiratory chain, and its defects are the main cause of mitochondrial disease. To understand the mechanisms regulating the extremely intricate biogenesis of this fundamental bioenergetic machine, we analyze the structural and functional consequences of the ablation of NDUFS3, a non-catalytic core subunit. We show that, in diverse mammalian cell types, a small amount of functional CI can still be detected in the complete absence of NDUFS3. In addition, we determine the dynamics of CI disassembly when the amount of NDUFS3 is gradually decreased. The process of degradation of the complex occurs in a hierarchical and modular fashion in which the ND4 module remains stable and bound to TMEM126A. We, thus, uncover the function of TMEM126A, the product of a disease gene causing recessive optic atrophy as a factor necessary for the correct assembly and function of CI., Graphical abstract, Highlights • A fraction of functional complex I assembles without the core subunit NDUFS3 • Complex I disassembly differentially affects its submodules • With NDUFS3 absent, the ND4-module of the P-distal domain remains mostly stable • The TMEM126A/OPA7 factor interacts with the ND4-module and is necessary for CI maturation, D’Angelo et al. show that eliminating NDUFS3 does not completely abolish respiratory complex I maturation. Differential degradation of complex I subunits belonging to different structural/functional modules is triggered by NDUFS3 repression. The ND4 module remains stable and is bound to TMEM126A, which is, here, identified as a complex I assembly factor.
Published: 2021

20. Inflammation causes remodeling of mitochondrial cytochrome c oxidase mediated by the bifunctional gene C15orf48

Author: Sally A. Clayton, Kalbinder K. Daley, Lucy MacDonald, Erika Fernandez-Vizarra, Giovanni Bottegoni, John D. O’Neil, Triin Major, Daniel Griffin, Qinqin Zhuang, Adeolu B. Adewoye, Kieran Woolcock, Simon W. Jones, Carl Goodyear, Aziza Elmesmari, Andrew Filer, Daniel A. Tennant, Stefano Alivernini, Christopher D. Buckley, Robert D. S. Pitceathly, Mariola Kurowska-Stolarska, and Andrew R. Clark
Subjects: Multidisciplinary, Settore MED/16 - REUMATOLOGIA, macromolecular substances, INGLESE
Abstract: Dysregulated mitochondrial function is a hallmark of immune-mediated inflammatory diseases. Cytochrome c oxidase (CcO), which mediates the rate-limiting step in mitochondrial respiration, is remodeled during development and in response to changes of oxygen availability, but there has been little study of CcO remodeling during inflammation. Here, we describe an elegant molecular switch mediated by the bifunctional transcript C15orf48, which orchestrates the substitution of the CcO subunit NDUFA4 by its paralog C15ORF48 in primary macrophages. Expression of C15orf48 is a conserved response to inflammatory signals and occurs in many immune-related pathologies. In rheumatoid arthritis, C15orf48 mRNA is elevated in peripheral monocytes and proinflammatory synovial tissue macrophages, and its expression positively correlates with disease severity and declines in remission. C15orf48 is also expressed by pathogenic macrophages in severe coronavirus disease 2019 (COVID-19). Study of a rare metabolic disease syndrome provides evidence that loss of the NDUFA4 subunit supports proinflammatory macrophage functions.
Published: 2021

21. Duplexing complexome profiling with SILAC to study human respiratory chain assembly defects

Author: Petra Páleníková, Massimo Zeviani, Erika Fernandez-Vizarra, Michal Minczuk, Michael E. Harbour, Anna Ghelli, Federica Prodi, Palenikova P., Harbour M.E., Prodi F., Minczuk M., Zeviani M., Ghelli A., and Fernandez-Vizarra E.
Subjects: 0301 basic medicine, Proteome, Complex III, Quantitative proteomics, Biophysics, Respiratory chain, Mitochondrial DNA mutation, Peptide, Complex IV, Hybrid Cells, Mass spectrometry, Biochemistry, SILAC, Mass Spectrometry, Electron Transport, Electron Transport Complex IV, Mitochondrial Proteins, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Stable isotope labeling by amino acids in cell culture, Quantitative proteomic, Mitochondrial Protein, Mitochondrial DNA mutations, Humans, Mitochondrial disease, Cytochromes b, Isotope Labeling, Mitochondria, chemistry.chemical_classification, Chemistry, Cell Biology, Hybrid Cell, 030104 developmental biology, Mitochondrial respiratory chain, Coenzyme Q – cytochrome c reductase, 030217 neurology & neurosurgery, Function (biology), Human
Abstract: Complexome Profiling (CP) combines size separation, by electrophoresis or other means, of native multimeric complexes with protein identification by mass spectrometry (MS). Peptide MS analysis of the multiple fractions in which the sample is separated, results in the creation of protein abundance profiles in function of molecular size, providing a visual output of the assembly status of a group of proteins of interest. Stable isotope labeling by amino acids in cell culture (SILAC) is an established quantitative proteomics technique that allows duplexing in the MS analysis as well as the comparison of relative protein abundances between the samples, which are processed and analyzed together. Combining SILAC and CP permitted the direct comparison of migration and abundance of the proteins present in the mitochondrial respiratory chain complexes in two different samples. This analysis, however, introduced a level of complexity in data processing for which bioinformatic tools had to be developed in order to generate the normalized protein abundance profiles. The advantages and challenges of using of this type of analysis for the characterization of two cell lines carrying pathological variants in MT-CO3 and MT-CYB is reviewed. An additional unpublished example of SILAC-CP of a cell line with an in-frame 18-bp deletion in MT-CYB is presented. In these cells, in contrast to other MT-CYB deficient models, a small proportion of complex III2 is formed and it is found associated with fully assembled complex I. This analysis also revealed a profuse accumulation of assembly intermediates containing complex III subunits UQCR10 and CYC1, as well as a profound early-stage complex IV assembly defect.
Published: 2021

22. Biallelic mutations in NDUFA8 cause complex I deficiency in two siblings with favorable clinical evolution

Author: Estibaliz Barredo, Laura Gort, Ranjani Parthasarathy, Xènia Ferrer-Cortès, Miguel Martín, Massimo Zeviani, Antonia Ribes, Erika Fernandez-Vizarra, Judit García-Villoria, Adrián González-Quintana, Olatz Ugarteburu, and Frederic Tort
Subjects: 0301 basic medicine, Male, Mitochondrial Diseases, Endocrinology, Diabetes and Metabolism, Mutant, Supercomplexes, Oxidative phosphorylation, 030105 genetics & heredity, Mitochondrion, Biology, medicine.disease_cause, Biochemistry, Complex I, Exome, Mitochondrial morphology, NDUFA8, OXPHOS, Whole Exome Sequencing, Oxidative Phosphorylation, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Western blot, Exome Sequencing, Genetics, medicine, Humans, Genetic Predisposition to Disease, Child, Molecular Biology, Gene, Female, Fibroblasts, Metabolism, Inborn Errors, Mitochondria, NADH Dehydrogenase, Siblings, Mutation, medicine.diagnostic_test, Inborn Errors, Molecular biology, Complementation, Metabolism, Failure to thrive, medicine.symptom, 030217 neurology & neurosurgery
Abstract: Isolated complex I (CI) deficiency is the most common cause of oxidative phosphorylation (OXPHOS) dysfunction. Whole-exome sequencing identified biallelic mutations in NDUFA8 (c.[293G > T]; [293G > T], encoding for an accessory subunit of CI, in two siblings with a favorable clinical evolution. The individuals reported here are practically asymptomatic, with the exception of slight failure to thrive and some language difficulties at the age of 6 and 9 years, respectively. These observations are remarkable since the vast majority of patients with CI deficiency, including the only NDUFA8 patient reported so far, showed an extremely poor clinical outcome. Western blot studies demonstrated that NDUFA8 protein was strongly reduced in the patients' fibroblasts and muscle extracts. In addition, there was a marked and specific decrease in the steady-state levels of CI subunits. BN-PAGE demonstrated an isolated defect in the assembly and the activity of CI with impaired supercomplexes formation and abnormal accumulation of CI subassemblies. Confocal microscopy analysis in fibroblasts showed rounder mitochondria and diminished branching degree of the mitochondrial network. Functional complementation studies demonstrated disease-causality for the identified mutation as lentiviral transduction with wild-type NDUFA8 cDNA restored the steady-state levels of CI subunits and completely recovered the deficient enzymatic activity in immortalized mutant fibroblasts. In summary, we provide additional evidence of the involvement of NDUFA8 as a mitochondrial disease-causing gene associated with altered mitochondrial morphology, CI deficiency, impaired supercomplexes formation, and very mild progression of the disease.
Published: 2020

23. A homozygous MRPL24 mutation causes a complex movement disorder and affects the mitoribosome assembly

Author: Michal Minczuk, Romina Oliva, Anna Ardissone, Federica Morani, Maria Marchese, Daniela Verrigni, Filippo M. Santorelli, Daniele Ghezzi, Teresa Rizza, Claudia Nesti, Giulia Trani, Alessandra Torraco, Massimo Zeviani, Christian Daniel Mutti, Gessica Vasco, Erika Fernandez-Vizarra, Rosalba Carrozzo, Michela Di Nottia, and Enrico Bertini
Subjects: 0301 basic medicine, Male, Ribosomal Proteins, Mitochondrial translation, Protein subunit, Mutant, MRPL24, Mitochondrial disorders, Mitochondrial protein synthesis, Mitoribosomes, Molecular modeling, Movement disorder, Protein interactions, Zebrafish, Animals, Cerebellum, Female, Humans, Infant, Leviviridae, Mitochondrial Proteins, Movement Disorders, Quadriceps Muscle, Gene mutation, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, Ribosomal protein, Mitochondrial ribosome, Missense mutation, Mitochondrial respiratory chain complex I, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Chemistry, Cell biology, 030104 developmental biology, Neurology, 030217 neurology & neurosurgery
Abstract: Mitochondrial ribosomal protein large 24 (MRPL24) is 1 of the 82 protein components of mitochondrial ribosomes, playing an essential role in the mitochondrial translation process. We report here on a baby girl with cerebellar atrophy, choreoathetosis of limbs and face, intellectual disability and a combined defect of complexes I and IV in muscle biopsy, caused by a homozygous missense mutation identified in MRPL24. The variant predicts a Leu91Pro substitution at an evolutionarily conserved site. Using human mutant cells and the zebrafish model, we demonstrated the pathological role of the identified variant. In fact, in fibroblasts we observed a significant reduction of MRPL24 protein and of mitochondrial respiratory chain complex I and IV subunits, as well a markedly reduced synthesis of the mtDNA-encoded peptides. In zebrafish we demonstrated that the orthologue gene is expressed in metabolically active tissues, and that gene knockdown induced locomotion impairment, structural defects and low ATP production. The motor phenotype was complemented by human WT but not mutant cRNA. Moreover, sucrose density gradient fractionation showed perturbed assembly of large subunit mitoribosomal proteins, suggesting that the mutation leads to a conformational change in MRPL24, which is expected to cause an aberrant interaction of the protein with other components of the 39S mitoribosomal subunit.
Published: 2020

24. Mitochondrial physiology: Gnaiger Erich et al ― MitoEAGLE Task Group

Author: Gnaiger, Erich, Aasander Frostner, Eleonor, Abdul Karim, Norwahidah, Abdel-Rahman, Engy Ali, Abumrad, Nada A, Acuna-Castroviejo, Dario, Adiele, Reginald C, Ahn, Bumsoo, Alencar, MB, Ali, Sameh S, Almeida, Angeles, Alton, Lesley, Alves, Marco G, Amati, Francesca, Amoedo, Nivea Dias, Amorim, Ricardo, Anderson, Ethan J, Andreadou, Ioanna, Antunes, Diana, Arago, Marc, Aral, Cenk, Arandarcikaite, Odeta, Arias-Reyes, Christian, Armand, Anne-Sophie, Arnould, Thierry, Avram, Vlad Florian, Axelrod, Christopher L, Bairam, Aida, Bailey, Damian M, Bajpeyi, Sudip, Bajzikova, Martina, Bakker, Barbara M, Barlow, Jonathan, Bardal, Tora, Banni, A, Bastos Sant'Anna Silva, Ana Carolina, Batterson, Philip, Battino, Maurizio, Bazil, Jason, Beard, Daniel A, Beleza, Jorge, Bednarczyk, Piotr, Bello, Fiona, Ben-Shachar, Dorit, Bento Guida, Jose Freitas, Bergdahl, Andreas, Berge, Rolf K, Bergmeister, Lisa, Bernardi, Paolo, Berridge, Michael V, Bettinazzi, Stefano, Bishop, David, Blier, Pierre U, Blindheim, Dan Filip, Boardman, Neoma T, Boetker, Hans Erik, Borchard, Sabine, Boros, Mihaly, Borsheim, Elisabet, Borras, Consuelo, Borutaite, Vilma, Botella, Javier, Bouillaud, Frederic, Bouitbir, Jamal, Boushel, Robert C, Bovard, Josh, Bravo-Sagua, Roberto, Breton, Sophie, Brown, David A, Brown, Guy C, Brown, Robert A, Brozinick, Joseph T, Buettner, Garry R, Burtscher, Johannes, Bustos, Matilde, Calabria, Elisa, Calbet, Jose A, Calzia, Enrico, Cannon, Daniel T, Cano Sanchez, Maria, Canto Alvarez, Carles, Cardinale, D, Cardoso, Luiza Helena Daltro, Carvalho, Eugenia, Casado Pinna, Marta, Cassar, Samantha, Castelo, Maria P, Castilho, Roger F, Cavalcanti-de-Albuquerque, Joao Paulo, Cecatto, Cristiane, Celen, Murat C, Cervinkova, Zuzana, Chabi, Beatrice, Chakrabarti, Lisa, Chakrabarti, Sasanka, Chaurasia, Bhagirath, Chen, Quan, Chicco, Adam J, Chinopoulos, Christos, Chowdhury, Subir K, Cizmarova, Beata, Clementi, Emilio, Coen, Paul M, Cohen, Bruce H, Coker, Robert H, Collin-Chenot, Anne, Coughlan, Melinda T, Coxito, Petro, Crisostomo, Luis, Crispim, Marcell, Crossland, Hannah, Dahdah, Norma, Dalgaard, Louise T, Dambrova, Maija, Danhelovska, Tereza, Darveau, Charles A, Darwin, Paula M, Das, Anibh M, Dash, Ranjan K, Davidova, Eliska, Davis, Michael S, Dayanidhi, Sudarshan, De Bem, Andreza Fabro, De Goede, Paul, De Palma, Clara, De Pinto, Vito, Dela, F, Dembinska-Kiec, Aldona, Detraux, Damien, Devaux, Yvan, Di Marcello, Marco, Di Paola, Floriana Jessica, Dias, Candida, Dias, Tania R, Diederich, Marc, Distefano, Giovanna, Djafarzadeh, Siamak, Doermann, Niklas, Doerrier, Carolina, Dong, Lan-Feng, Donnelly, Chris, Drahota, Zdenek, Duarte, Filipe Valente, Dubouchaud, Herve, Duchen, Michael R, Dumas, Jean-Francois, Durham, William J, Dymkowska, Dorota, Dyrstad, Sissel E, Dyson, Alex, Dzialowski, Edward M, Eaton, Simon, Ehinger, Johannes, Elmer, Eskil, Endlicher, Rene, Engin, Ayse B, Escames, Germaine, Evinova, Andrea, Ezrova, Zuzana, Falk, Marni Joy, Fell, David A, Ferdinandy, Peter, Ferko, Miroslav, Fernandez-Ortiz, Marisol, Erika, Fernandez-Vizarra, Ferreira, Julio Cesar Batista, Ferreira, Rita, Ferri, Alessandra, Festuccia, WT, Fessel, Joshua P, Filipovska, Aleksandra, Fisar, Zdenek, Fischer, Christine, Fischer, Michael, Fisher, Gordon, Fisher, Joshua J, Fontanesi, Flavia, Forbes-Hernandez, Tamara Y, Ford, Ellen, Fornaro, Mara, Fuertes Agudo, Marina, Fulton, Montana, Galina, Antonio, Galkin, Alexander, Gallee, Leon, Galli, Gina L, Gama Perez, Pau, Gan, Zhenji, Ganetzky, Rebecca, Gao, Yun, Garcia, Geovana S, Garcia-Rivas, Gerardo, Garcia-Roves, Pablo Miguel, Garcia-Souza, Luiz Felipe, Garlid, Keith D, Garrabou, Gloria, Garten, Antje, Gastaldelli, Amalia, Gayen, Jiaur, Genders, Amanda J, Genova, Maria Luisa, Giampieri, Francesca, Glatz, Jan FC, Giovarelli, Matteo, Goikoetxea Usandizaga, Naroa, Goncalo Teixeira da Silva, Rui, Goncalves, Debora Farina, Gonzalez-Armenta, Jenny L, Gonzalez-Francesqua, A, Gonzalez-Freire, Marta, Gonzalo, Hugo, Goodpaster, Bret H, Gorr, Thomas A, Gourlay, Campbell W, Grams, Bente, Granata, Cesare, Grefte, Sander, Grilo, Luis, Guarch, Meritxell Espino, Gueguen, Naig, Gumeni, Sentiljana, Haas, Clarissa B, Haavik, Jan, Hachmo, Yafit, Haendeler, Judith, Haider, Markus, Hajrulahovic, Anesa, Hamann, Andrea, Han, Jin, Han, Woo Hyun, Hancock, Chad R, Hand, Steven C, Handl, Jiri, Hansikova, Hana, Hardee, Justin P, Hargreaves, Ian P, Harper, Mary Ellen, Harrison, David K, Hassan, Hazirah, Hatakova, Zuzana, Hausenloy, Derek J, Heales, Simon JR, Heiestad, Christina, Hellgren, Kim T, Henrique, Alexandrino, Hepple, Russell T, Hernansanz-Agustin, Pablo, Hewakapuge, Sudinna, Hickey, Anthony J, Ho, Dieu Hien, Hoehn, Kyle L, Hoel, Frederik, Holland, Olivia J, Holloway, Graham P, Holzner, Lorenz, Hoppel, Charles L, Hoppeler, H, Hoppel, Florian, Houstek, Josef, Huete-Ortega, Maria, Hyrossova, Petra, Iglesias-Gonzalez, Javier, Indiveri, Cesare, Irving, Brian A, Isola, Raffaella, Iyer, Shilpa, Jackson, Christophe B, Jadiya, Pooja, Jana, Prado Fabian, Jandeleit-Dahm, K, Jang, David H, Jang, Young C, Janowska, Joanna, Jansen, Kirsten, Jansen-Duerr, Pidder, Jansone, Baiba, Jarmuszkiewicz, Wieslawa, Jaskiewicz, Anna, Jaspers, Richard T, Jedlicka, Jan, Jerome, Estaquier, Jespersen, Nichlas R, Jha, Rajan K, Joseph, Vincent, Juhasz, Laszlo, Jurczak, Michael J, Jurk, Diana, Kaambre, Tuuli, Kaczor, Jan J, Kainulainen, Heikki, Kampa, Rafal Pawel, Kandel, Sunil M, Kane, Daniel A, Kapferer, Werner, Kapnick, Senta, Kappler, Lisa, Karabatsiakis, Alexander, Karavaeva, Iuliia, Karkucinska-Wieckowska, Agnieszka, Kaur, Sarbjot, Keijer, Jaap, Keller, Markus A, Keppner, Gloria, Khamoui, Andy V, Kidere, Dita, Kilbaugh, Todd, Kim, Hyoung Kyu, Kim, Julian KS, Kimoloi, Sammy, Klepinin, Aleksandr, Klepinina, Lyudmila, Klingenspor, Martin, Klocker, Helmut, Komlódi, Timea, Kolasa, Iris, Koopman, Werner JH, Kopitar-Jerala, Natasa, Kowaltowski, Alicia J, Kozlov, Andrey V, Krajcova, Adela, Krako Jakovljevic, Nina, Kristal, Bruce S, Krycer, Jamer R, Kuang, Jujiao, Kucera, Otto, Kuka, Janis, Kwak, Hyo Bum, Kwast, Kurt, Kwon, Oh Sung, Laasmaa, Martin, Labieniec-Watala, Magdalena, Lai, Nicola, Lalic, Nebojsa M, Land, John M, Lane, Nick, Laner, Verena, Lanza, Ian R, Laouafa, Sofien, Larsen, Steen, Larsen, Terje S, Lavery, Gareth G, Lazou, Antigone, Ledo, Ana Margarida, Lee, Hong Kyu, Leeuwenburgh, Christiaan, Lehti, Maarit, Lemieux, Helene, Lenaz, Giorgio, Lerfall, Jorgen, Li, Pingan A, Li Puma, Lance, Liang, Liping, Liepins, Edgars, Lin, Chien-Te, Liu, Jiankang, Lopez, Luis C, Lucchinetti, Eliana, Ma, Tao, Macedo, Maria P, Machado, Ivo F, Maciej, Sarah, MacMillan-Crow, Lee Ann, Magalhaes, Jose, Magri, Andrea, Majtnerova, Pavlina, Makarova, Elina, Makrecka-Kuka, Marina, Malik, Afshan N, Marcouiller, Francois, Marechal, Amandine, Markova, Michaela, Markovic, Ivanka, Martin, Daniel S, Martins, Ana Dias, Martins, Joao D, Maseko, Tumisang Edward, Maull, Felicia, Mazat, Jean Pierre, McKenna, Helen T, McKenzie, Matthew, McMillan, Duncan GG, McStay, Gavin P, Menze, Michael A, Mendham, Amy, Mercer, John R, Merz, Tamara, Messina, Angela, Meszaros, Andras T, Methner, Axel, Michalak, Slawomir, Mila Guasch, Maria, Minuzzi, Luciele M, Misirkic Marjanovic, Maja, Moellering, Douglas R, Moisoi, Nicoleta, Molina, Anthony JA, Montaigne, David, Moore, Anthony L, Moore, Christy, Moreau, Kerrie, Moreira, Bruno P, Moreno-Sanchez, Rafael, Mracek, Tomas, Muccini, Anna Maria, Muntane, Jordi, Muntean, Danina M, Murray, Andrew J, Musiol, Eva, Nabben, Miranda, Nair, K Sreekumaran, Nehlin, Jan O, Nemec, Michal, Nesci, Salvatore, Neufer, P Darrell, Neuzil, Jiri, Neviere, Remi, Newsom, Sean A., Norman, Jennifer, Nozickova, Katerina, Nunes, Sara, Nuoffer, Jean-Marc, O'Brien, Kristin, O'Brien, Katie A, O'Gorman, Donal, Olgar, Yusuf, Oliveira, Ben, Oliveira, Jorge, Oliveira, Marcus F, Oliveira, Marcos Tulio, Oliveira, Pedro F, Oliveira, Paulo J, Olsen, Rolf Erik, Orynbayeva, Zulfiya, Osiewacz, Heinz D, Paez, Hector, Pak, Youngmi K, Pallotta, Maria L, Palmeira, Carlos M, Parajuli, Nirmala, Passos, Joao F, Passrugger, Manuela, Patel, Hemal H, Pavlova, Nadia, Pavlovic, Kasja, Pecina, Petr, Pedersen, Tina M, Perales, Jose Carlos, Pereira da Silva Grilo da Silva, Filomena, Pereira, Rita, Perez Valencia, Juan A, Perks, Kara L, Pesta, Dominik, Petit, Patrice X, Pettersen Nitschke, Ina Katrine, Pichaud, Nicolas, Pichler, Irene, Piel, Sarah, Pietka, Terri A, Pinho, Sonia A, Pino, Maria F, Pirkmajer, Sergej, Place, Nicolas, Plangger, Mario, Porter, Craig, Porter, Richard K, Preguica, Ines, Procaccio, Vincent, Prochownik, Edward V, Prola, Alexandre, Pulinilkunnil, Thomas, Puskarich, Michael A, Puurand, Marju, Radenkovic, Filip, Ramzan, Rabia, Rattan, Suresh IS, Reano, Simone, Reboredo, Patricia, Rees, Bernard B, Renner-Sattler, Kathrin, Rial, Eduardo, Robinson, Matthew M, Roden, Michael, Rodrigues, Ana Sofia, Rodriguez, Enrique, Rodriguez-Enriquez, Sara, Roesland, Gro Vatne, Rolo, Anabela Pinto, Ropelle, Eduardo R, Roshanravan, Baback, Rossignol, Rodrigue, Rossiter, Harry B, Rousar, Tomas, Rubelj, Ivica, Rybacka-Mossakowska, Joanna, Saada, Ann, Safaei, Zahra, Sarlak, Saharnaz, Salin, Karine, Salvadego, Desy, Sandi, Carmen, Saner, Nicholas, Santos, Diana, Sanz, Alberto, Sardao, Vilma, Sazanov, Leonid A, Scaife, Paula, Scatena, Roberto, Schartner, Melanie, Scheibye-Knudsen, Morten, Schilling, Jan M, Schlattner, Uwe, Schmitt, Sabine, Schneider Gasser, Edith Mariane, Schoenfeld, Peter, Schots, Pauke C, Schulz, Rainer, Schwarzer, Christoph, Scott, Graham R, Selman, Colin, Sendon, Pamella Marie, Shabalina, Irina G, Sharma, Pushpa, Sharma, Vipin, Shevchuk, Igor, Shirazi, Reza, Shiroma, Jonathan G, Siewiera, Karolina, Silber, Ariel M, Silva, Ana Maria, Sims, Carrie A, Singer, Dominique, Singh, Brijesh Kumar, Skolik, Robert A, Smenes, Benedikte Therese, Smith, James, Soares, Félix Alexandre Antunes, Sobotka, Ondrej, Sokolova, Inna, Solesio Torregrosa, M De la Encarnacion, Soliz, Jorge, Sonkar, Vijay K, Sova, Marina, Sowton, Alice P, Sparagna, Genevieve C, Sparks, Lauren M, Spinazzi, Marco, Stankova, Pavla, Starr, Jonathan, Stary, Creed, Stefan, Eduard, Stelfa, Gundega, Stepto, Nigel K, Stevanovic, Jelena, Stiban, Johnny, Stier, Antoine, Stocker, Roland, Storder, Julie, Sumbalova, Zuzana, Suomalainen, Wartiovaara Anu, Suravajhala, Prashanth, Svalbe, Baiba, Swerdlow, Russel H, Swiniuch, Daria, Szabo, Ildiko, Szewczyk, Adam, Szibor, Marten, Tanaka, Masashi, Tandler, Bernard, Tarnopolsky, Mark A, Tausan, Daniel, Tavernarakis, Nektarios, Tepp, Kersti, Teodoro, J, Thakkar, Himani, Thapa, Maheshwo, Thyfault, John P, Tomar, Dhanendra, Ton, Riccardo, Torp, May-Kristin, Torres-Quesada, Omar, Towheed, Atif, Treberg, Jason R, Tretter, Laszlo, Trewin, Adam J, Trifunovic, Aleksandra, Trivigno, Catherine, Tronstad, Karl Johan, Trougakos, Ioannis P, Truu, Laura, Tuncay, Erkan, Turan, Belma, Tyrrell, Daniel J, Urban, Tomas, Urner, Sofia, Valentine, Joseph Marco, Van Bergen, Nicole J, Van der Ende, Miranda, Varricchio, Frederick, Vaupel, Peter, Vella, Joanna, Vendelin, Marko, Verdaguer, IB, Vercesi, Anibal E, Vernerova, Andrea, Victor, Victor Manuel, Vieira Ligo Teixeira, Camila, Vidimce, Josif, Viel, Christian, Vieyra, Adalberto, Vilks, Karlis, Villena, Joseph A, Vincent, Vinnyfred, Vinogradov, Andrey D, Viscomi, Carlo, Vitorino, Rui Miguel Pinheiro, Vlachaki Walker, Julia, Vogt, Sebastian, Volani, Chiara, Volska, Kristine, Votion, Dominique-Marie, Vujacic-Mirski, Ksenija, Wagner, Brett A, Ward, Marie Louise, Warnsmann, Verena, Wasserman, David H, Watala, Cezary, Wei, Yau-Huei, Weinberger, Klaus M, White, Sarah, Whitfield, Jamie, Wickert, Anika, Wieckowski, Mariusz R, Wiesner, Rudolf J, Williams, Caroline M, Winwood-Smith, Hugh, Wohlgemuth, Stephanie E, Wohlwend, Martin, Wolff, Jonci Nikolai, Wrutniak-Cabello, Chantal, Wuest, Rob C I, Yokota, Takashi, Zablocki, Krzysztof, Zanon, Alessandra, Zanou, Nadege, Zaugg, Kathrin, Zaugg, Michael, Zdrazilova, Lucie, Zhang, Yong, Zhang, Yi Zhu, Zikova, Alena, Zischka, Hans, Zorzano, Antonio, Zujovic, Tijana, Zurmanova, Jitka, Zvejniece, Liga, Lagarrigue, Sylviane, Munro, Daniel, Pereira, Susana, Laranjinha, Joäo, Hecker, Matthias, Jusic, Amela, Prigione, Alessandro, Sommer, Natascha, Weissig, Volkmar, Guida, Bento, G, John G, Jones, JG, AMS - Tissue Function & Regeneration, AMS - Rehabilitation & Development, Physiology, Mito-Eagle - Evolution-Age-Gender-Lifestyle-Environment (Mito-Eagle), Oroboros Instruments, Dynamique Musculaire et Métabolisme (DMEM), Université de Montpellier (UM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Gnaiger Erich, Aasander Frostner Eleonor, Abdul Karim Norwahidah, Abdel-Rahman Engy Ali, Abumrad Nada A, Acuna-Castroviejo Dario, Adiele Reginald C, Ahn Bumsoo, Alencar Mayke Bezerra, Ali Sameh S, Almeida Angeles, Alton Lesley, Alves Marco G, Amati Francesca, Amoedo Nivea Dias, Amorim Ricardo, Anderson Ethan J, Andreadou Ioanna, Antunes Diana, Arago Marc, Aral Cenk, Arandarcikaite Odeta, Arias-Reyes Christian, Armand Anne-Sophie, Arnould Thierry, Avram Vlad F, Axelrod Christopher L, Bailey Damian M, Bairam Aida, Bajpeyi Sudip, Bajzikova Martina, Bakker Barbara M, Banni Aml, Bardal Tora, Barlow J, Bastos Sant'Anna Silva Ana Carolina, Batterson Philip M, Battino Maurizio, Bazil Jason N, Beard Daniel A, Bednarczyk Piotr, Beleza Jorge, Bello Fiona, Ben-Shachar Dorit, Bento Guida Jose Freitas, Bergdahl Andreas, Berge Rolf K, Bergmeister Lisa, Bernardi Paolo, Berridge Michael V, Bettinazzi Stefano, Bishop David J, Blier Pierre U, Blindheim Dan Filip, Boardman Neoma T, Boetker Hans Erik, Borchard Sabine, Boros Mihaly, Boersheim Elisabet, Borras Consuelo, Borutaite Vilma, Botella Javier, Bouillaud Frederic, Bouitbir Jamal, Boushel Robert C, Bovard Josh, Bravo-Sagua Roberto, Breton Sophie, Brown David A, Brown Guy C, Brown Robert Andrew, Brozinick Joseph T, Buettner Garry R, Burtscher Johannes, Bustos Matilde, Calabria Elisa, Calbet Jose AL, Calzia Enrico, Cannon Daniel T, Cano Sanchez Maria Consolacion, Canto Alvarez Carles, Cardinale Daniele A, Cardoso Luiza HD, Carvalho Eugenia, Casado Pinna Marta, Cassar Samantha, Castelo Rueda Maria Paulina, Castilho Roger F, Cavalcanti-de-Albuquerque Joao Paulo, Cecatto Cristiane, Celen Murat C, Cervinkova Zuzana, Chabi Beatrice, Chakrabarti Lisa, Chakrabarti Sasanka, Chaurasia Bhagirath, Chen Quan, Chicco Adam J, Chinopoulos Christos, Chowdhury Subir Kumar, Cizmarova Beata, Clementi Emilio, Coen Paul M, Cohen Bruce H, Coker Robert H, Collin-Chenot Anne, Coughlan Melinda T, Coxito Pedro, Crisostomo Luis, Crispim Marcell, Crossland Hannah, Dahdah Norma Ramon, Dalgaard Louise T, Dambrova Maija, Danhelovska Tereza, Darveau Charles-A, Darwin Paula M, Das Anibh Martin, Dash Ranjan K, Davidova Eliska, Davis Michael S, Dayanidhi Sudarshan, De Bem Andreza Fabro, De Goede Paul, De Palma Clara, De Pinto Vito, Dela Flemming, Dembinska-Kiec Aldona, Detraux Damian, Devaux Yvan, Di Marcello Marco, Di Paola Floriana Jessica, Dias Candida, Dias Tania R, Diederich Marc, Distefano Giovanna, Djafarzadeh Siamak, Doermann Niklas, Doerrier Carolina, Dong Lan-Feng, Donnelly Chris, Drahota Zdenek, Duarte Filipe Valente, Dubouchaud Herve, Duchen Michael R, Dumas Jean-Francois, Durham William J, Dymkowska Dorota, Dyrstad Sissel E, Dyson Alex, Dzialowski Edward M, Eaton Simon, Ehinger Johannes K, Elmer Eskil, Endlicher Rene, Engin Ayse Basak, Escames Germaine, Evinova Andrea, Ezrova Zuzana, Falk Marni J, Fell David A, Ferdinandy Peter, Ferko Miroslav, Fernandez-Ortiz Marisol, Fernandez-Vizarra Erika, Ferreira Julio Cesar B, Ferreira Rita Maria P, Ferri Alessandra, Fessel Joshua Patrick, Festuccia William T, Filipovska Aleksandra, Fisar Zdenek, Fischer Christine, Fischer Michael J, Fisher Gordon, Fisher Joshua J, Fontanesi Flavia, Forbes-Hernandez Tamara Y, Ford Ellen, Fornaro Mara, Fuertes Agudo Marina, Fulton Montana, Galina Antonio, Galkin Alexander, Gallee Leon, Galli Gina L J, Gama Perez Pau, Gan Zhenji, Ganetzky Rebecca, Gao Yun, Garcia Geovana S, Garcia-Rivas Gerardo, Garcia-Roves Pablo Miguel, Garcia-Souza Luiz F, Garlid Keith D, Garrabou Gloria, Garten Antje, Gastaldelli Amalia, Gayen Jiaur, Genders Amanda J, Genova Maria Luisa, Giampieri Francesca, Giovarelli Matteo, Glatz Jan FC, Goikoetxea Usandizaga Naroa, Goncalo Teixeira da Silva Rui, Goncalves Debora Farina, Gonzalez- Armenta Jenny L, Gonzalez-Franquesa Alba, Gonzalez-Freire Marta, Gonzalo Hugo, Goodpaster Bret H, Gorr Thomas A, Gourlay Campbell W, Grams Bente, Granata Cesare, Grefte Sander, Grilo Luis, Guarch Meritxell Espino, Gueguen Naig, Gumeni Sentiljana, Haas Clarissa, Haavik Jan, Hachmo Yafit, Haendeler Judith, Haider Markus, Hajrulahovic Anesa, Hamann Andrea, Han Jin, Han Woo Hyun, Hancock Chad R, Hand Steven C, Handl Jiri, Hansikova Hana, Hardee Justin P, Hargreaves Iain P, Harper Mary- Ellen, Harrison David K, Hassan Hazirah, Hatokova Zuzana, Hausenloy Derek J, Heales Simon JR, Hecker Matthias, Heiestad Christina, Hellgren Kim T, Henrique Alexandrino, Hepple Russell T, Hernansanz- Agustin Pablo, Hewakapuge Sudinna, Hickey Anthony J, Ho Dieu Hien, Hoehn Kyle L, Hoel Fredrik, Holland Olivia J, Holloway Graham P, Holzner Lorenz, Hoppel Charles L, Hoppel Florian, Hoppeler Hans, Houstek Josef, Huete-Ortega Maria, Hyrossova Petra, Iglesias-Gonzalez Javier, Indiveri Cesare, Irving Brian A, Isola Raffaella, Iyer Shilpa, Jackson Christopher Benjamin, Jadiya Pooja, Jana Prado Fabian, Jandeleit-Dahm Karin, Jang David H, Jang Young Charles, Janowska Joanna, Jansen Kirsten M, Jansen-Duerr Pidder, Jansone Baiba, Jarmuszkiewicz Wieslawa, Jaskiewicz Anna, Jaspers Richard T, Jedlicka Jan, Jerome Estaquier, Jespersen Nichlas Riise, Jha Rajan Kumar, Jones John G, Joseph Vincent, Juhasz Laszlo, Jurczak Michael J, Jurk Diana, Jusic Amela, Kaambre Tuuli, Kaczor Jan Jacek, Kainulainen Heikki, Kampa Rafal Pawel, Kandel Sunil Mani, Kane Daniel A, Kapferer Werner, Kapnick Senta, Kappler Lisa, Karabatsiakis Alexander, Karavaeva Iuliia, Karkucinska-Wieckowska Agnieszka, Kaur Sarbjot, Keijer Jaap, Keller Markus A, Keppner Gloria, Khamoui Andy V, Kidere Dita, Kilbaugh Todd, Kim Hyoung Kyu, Kim Julian KS, Kimoloi Sammy, Klepinin Aleksandr, Klepinina Lyudmila, Klingenspor Martin, Klocker Helmut, Kolassa Iris, Komlodi Timea, Koopman Werner JH, Kopitar-Jerala Natasa, Kowaltowski Alicia J, Kozlov Andrey V, Krajcova Adela, Krako Jakovljevic Nina, Kristal Bruce S, Krycer James R, Kuang Jujiao, Kucera Otto, Kuka Janis, Kwak Hyo Bum, Kwast Kurt E, Kwon Oh Sung, Laasmaa Martin, Labieniec-Watala Magdalena, Lagarrigue Sylviane, Lai Nicola, Lalic Nebojsa M, Land John M, Lane Nick, Laner Verena, Lanza Ian R, Laouafa Sofien, Laranjinha Joao, Larsen Steen, Larsen Terje S, Lavery Gareth G, Lazou Antigone, Ledo Ana Margarida, Lee Hong Kyu, Leeuwenburgh Christiaan, Lehti Maarit, Lemieux Helene, Lenaz Giorgio, Lerfall Joergen, Li Pingan Andy, Li Puma Lance, Liang Liping, Liepins Edgars, Lin Chien-Te, Liu Jiankang, Lopez Garcia Luis Carlos, Lucchinetti Eliana, Ma Tao, Macedo Maria Paula, Machado Ivo F, Maciej Sarah, MacMillan-Crow Lee Ann, Magalhaes Jose, Magri Andrea, Majtnerova Pavlina, Makarova Elina, Makrecka-Kuka Marina, Malik Afshan N, Marcouiller Francois, Marechal Amandine, Markova Michaela, Markovic Ivanka, Martin Daniel S, Martins Ana Dias, Martins Joao D, Maseko Tumisang Edward, Maull Felicia, Mazat Jean-Pierre, McKenna Helen T, McKenzie Matthew, McMillan Duncan GG, McStay Gavin P, Mendham Amy, Menze Michael A, Mercer John R, Merz Tamara, Messina Angela, Meszaros Andras, Methner Axel, Michalak Slawomir, Mila Guasch Maria, Minuzzi Luciele M, Misirkic Marjanovic Maja, Moellering Douglas R, Moisoi Nicoleta, Molina Anthony JA, Montaigne David, Moore Anthony L, Moore Christy, Moreau Kerrie, Moreira Bruno P, Moreno-Sanchez Rafael, Mracek Tomas, Muccini Anna Maria, Munro Daniel, Muntane Jordi, Muntean Danina M, Murray Andrew James, Musiol Eva, Nabben Miranda, Nair K Sreekumaran, Nehlin Jan O, Nemec Michal, Nesci Salvatore, Neufer P Darrell, Neuzil Jiri, Neviere Remi, Newsom Sean A, Norman Jennifer, Nozickova Katerina, Nunes Sara, Nuoffer Jean-Marc, O'Brien Kristin, O'Brien Katie A, O'Gorman Donal, Olgar Yusuf, Oliveira Ben, Oliveira Jorge, Oliveira Marcus F, Oliveira Marcos Tulio, Oliveira Pedro Fontes, Oliveira Paulo J, Olsen Rolf Erik, Orynbayeva Zulfiya, Osiewacz Heinz D, Paez Hector, Pak Youngmi Kim, Pallotta Maria Luigia, Palmeira Carlos, Parajuli Nirmala, Passos Joao F, Passrugger Manuela, Patel Hemal H, Pavlova Nadia, Pavlovic Kasja, Pecina Petr, Pedersen Tina M, Perales Jose Carles, Pereira da Silva Grilo da Silva Filomena, Pereira Rita, Pereira Susana P, Perez Valencia Juan Alberto, Perks Kara L, Pesta Dominik, Petit Patrice X, Pettersen Nitschke Ina Katrine, Pichaud Nicolas, Pichler Irene, Piel Sarah, Pietka Terri A, Pinho Sonia A, Pino Maria F, Pirkmajer Sergej, Place Nicolas, Plangger Mario, Porter Craig, Porter Richard K, Preguica Ines, Prigione Alessandro, Procaccio Vincent, Prochownik Edward V, Prola Alexandre, Pulinilkunnil Thomas, Puskarich Michael A, Puurand Marju, Radenkovic Filip, Ramzan Rabia, Rattan Suresh IS, Reano Simone, Reboredo-Rodriguez Patricia, Rees Bernard B, Renner-Sattler Kathrin, Rial Eduardo, Robinson Matthew M, Roden Michael, Rodrigues Ana Sofia, Rodriguez Enrique, Rodriguez-Enriquez Sara, Roesland Gro Vatne, Rohlena Jakub, Rolo Anabela Pinto, Ropelle Eduardo R, Roshanravan Baback, Rossignol Rodrigue, Rossiter Harry B, Rousar Tomas, Rubelj Ivica, Rybacka-Mossakowska Joanna, Saada Reisch Ann, Safaei Zahra, Salin Karine, Salvadego Desy, Sandi Carmen, Saner Nicholas, Santos Diana, Sanz Alberto, Sardao Vilma, Sarlak Saharnaz, Sazanov Leonid A, Scaife Paula, Scatena Roberto, Schartner Melanie, Scheibye-Knudsen Morten, Schilling Jan M, Schlattner Uwe, Schmitt Sabine, Schneider Gasser Edith Mariane, Schoenfeld Peter, Schots Pauke C, Schulz Rainer, Schwarzer Christoph, Scott Graham R, Selman Colin, Sendon Pamella Marie, Shabalina Irina G, Sharma Pushpa, Sharma Vipin, Shevchuk Igor, Shirazi Reza, Shiroma Jonathan G, Siewiera Karolina, Silber Ariel M, Silva Ana Maria, Sims Carrie A, Singer Dominique, Singh Brijesh Kumar, Skolik Robert A, Smenes Benedikte Therese, Smith James, Soares Felix Alexandre Antunes, Sobotka Ondrej, Sokolova Inna, Solesio Maria E, Soliz Jorge, Sommer Natascha, Sonkar Vijay K, Sova Marina, Sowton Alice P, Sparagna Genevieve C, Sparks Lauren M, Spinazzi Marco, Stankova Pavla, Starr Jonathan, Stary Creed, Stefan Eduard, Stelfa Gundega, Stepto Nigel K, Stevanovic Jelena, Stiban Johnny, Stier Antoine, Stocker Roland, Storder Julie, Sumbalova Zuzana, Suomalainen Anu, Suravajhala Prashanth, Svalbe Baiba, Swerdlow Russell H, Swiniuch Daria, Szabo Ildiko, Szewczyk Adam, Szibor Marten, Tanaka Masashi, Tandler Bernard, Tarnopolsky Mark A, Tausan Daniel, Tavernarakis Nektarios, Teodoro Joao Soeiro, Tepp Kersti, Thakkar Himani, Thapa Maheshwor, Thyfault John P, Tomar Dhanendra, Ton Riccardo, Torp May-Kristin, Torres-Quesada Omar, Towheed Atif, Treberg Jason R, Tretter Laszlo, Trewin Adam J, Trifunovic Aleksandra, Trivigno Catherine, Tronstad Karl Johan, Trougakos Ioannis P, Truu Laura, Tuncay Erkan, Turan Belma, Tyrrell Daniel J, Urban Tomas, Urner Sofia, Valentine Joseph Marco, Van Bergen Nicole J, Van der Ende Miranda, Varricchio Frederick, Vaupel Peter, Vella Joanna, Vendelin Marko, Vercesi Anibal E, Verdaguer Ignasi Bofill, Vernerova Andrea, Victor Victor Manuel, Vieira Ligo Teixeira Camila, Vidimce Josif, Viel Christian, Vieyra Adalberto, Vilks Karlis, Villena Josep A, Vincent Vinnyfred, Vinogradov Andrey D, Viscomi Carlo, Vitorino Rui Miguel Pinheiro, Vlachaki Walker Julia, Vogt Sebastian, Volani Chiara, Volska Kristine, Votion Dominique-Marie, Vujacic-Mirski Ksenija, Wagner Brett A, Ward Marie Louise, Warnsmann Verena, Wasserman David H, Watala Cezary, Wei Yau-Huei, Weinberger Klaus M, Weissig Volkmar, White Sarah Haverty, Whitfield Jamie, Wickert Anika, Wieckowski Mariusz R, Wiesner Rudolf J, Williams Caroline M, Winwood-Smith Hugh, Wohlgemuth Stephanie E, Wohlwend Martin, Wolff Jonci Nikolai, Wrutniak-Cabello Chantal, Wuest Rob CI, Yokota Takashi, Zablocki Krzysztof, Zanon Alessandra, Zanou Nadege, Zaugg Kathrin, Zaugg Michael, Zdrazilova Lucie, Zhang Yong, Zhang Yizhu, Zikova Alena, Zischka Hans, Zorzano Antonio, Zujovic Tijana, Zurmanova Jitka, Zvejniece Liga
Subjects: uncoupling, MitoPedia: Respiratory states, SI - The International System of Units, IUPAC, Coupling control, Mitochondrial preparations, Protonmotive force, Uncoupling, Oxidative phosphorylation, Phosphorylation efficiency, Electron transfer-pathway, LEAK-respiration, Residual oxygen consumption, Normalization of rate, Flow, Flux, Flux control ratio, Mitochondrial marker, Cell count, Oxygen, [SDV]Life Sciences [q-bio], coupling control, protonmotive force, oxidative phosphorylation, mitochondrial respiratory control, State 4, electron transfer, State 2, State 3, Mitochondrial physiology, residual oxygen consumption, flux, normalization, ion leak and slip compensatory state, efficiency, electron transfer system, flow, mitochondrial physiology, oxygen, mitochondrial preparations, proton leak
Abstract: As the knowledge base and importance of mitochondrial physiology to evolution, health and diseaseexpands, the necessity for harmonizing the terminologyconcerning mitochondrial respiratory states and rates has become increasingly apparent. Thechemiosmotic theoryestablishes the mechanism of energy transformationandcoupling in oxidative phosphorylation. Theunifying concept of the protonmotive force providestheframeworkfordeveloping a consistent theoretical foundation ofmitochondrial physiology and bioenergetics.We followthe latest SI guidelines and those of the International Union of Pure and Applied Chemistry(IUPAC)onterminology inphysical chemistry, extended by considerationsofopen systems and thermodynamicsof irreversible processes.Theconcept-driven constructive terminology incorporates the meaning of each quantity and alignsconcepts and symbols withthe nomenclature of classicalbioenergetics. We endeavour to provide a balanced view ofmitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes.Uniform standards for evaluation of respiratory states and rates will ultimatelycontribute BEC 2020.1 doi:10.26124/bec:2020-0001.v1www.bioenergetics-communications.org3of 44to reproducibility between laboratories and thussupport the development of datarepositoriesof mitochondrial respiratory function in species, tissues, and cells.Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery.
Published: 2020

25. Assembly of mammalian oxidative phosphorylation complexes I–V and supercomplexes

Author: Alba Signes, Erika Fernandez-Vizarra, Fernandez-Vizarra, Erika [0000-0002-2469-142X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Mitochondrial disease, oxidative phosphorylation, Oxidative phosphorylation, Review Article, Mitochondrion, Biochemistry, Cofactor, Electron Transport, 03 medical and health sciences, Multienzyme Complexes, medicine, atp synthase, Animals, Humans, Inner mitochondrial membrane, Molecular Biology, Review Articles, chemistry.chemical_classification, Mammals, biology, ATP synthase, Chemistry, electron transport chain, medicine.disease, Electron transport chain, Cell biology, Mitochondria, 030104 developmental biology, Enzyme, mitochondria, respiratory chain complex assembly, Oxidative Phosphorylation, biology.protein
Abstract: The assembly of the five oxidative phosphorylation system (OXPHOS) complexes in the inner mitochondrial membrane is an intricate process. The human enzymes comprise core proteins, performing the catalytic activities, and a large number of ‘supernumerary’ subunits that play essential roles in assembly, regulation and stability. The correct addition of prosthetic groups as well as chaperoning and incorporation of the structural components require a large number of factors, many of which have been found mutated in cases of mitochondrial disease. Nowadays, the mechanisms of assembly for each of the individual complexes are almost completely understood and the knowledge about the assembly factors involved is constantly increasing. On the other hand, it is now well established that complexes I, III and IV interact with each other, forming the so-called respiratory supercomplexes or ‘respirasomes’, although the pathways that lead to their formation are still not completely clear. This review is a summary of our current knowledge concerning the assembly of complexes I–V and of the supercomplexes.
Published: 2018

26. Modelling the human mitochondrial disease related to APOPT1 in Drosophila melanogaster

Author: Michele Brischigliaro, Corra, Samantha, Tregnago, Claudia, Erika, Fernandez-Vizarra, Massimo Zeviani, RODOLFO COSTA, and Cristiano De Pitta
Published: 2019

27. Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7

Author: Jarosław Poznański, Markus Deckers, Agnieszka Chacinska, Erika Fernandez-Vizarra, Sven Dennerlein, Michal Dadlez, Michał Wasilewski, Zaneta Bugajska, Cristiane Benincá, Karthik Mohanraj, Paulina Sakowska, Peter Rehling, Dominik Cysewski, Massimo Zeviani, and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, COA7/RESA1, Respiratory chain, Mitochondrion, Mitochondrial Membrane Transport Proteins, 0302 clinical medicine, Cytosol, Mitochondrial Precursor Protein Import Complex Proteins, Disulfides, Research Articles, mitochondrial disease, proteasome, protein degradation, protein import, Electron Transport, Fibroblasts, HEK293 Cells, HeLa Cells, Humans, Mitochondria, Mitochondrial Membranes, Mitochondrial Proteins, Mutant Proteins, Mutation, Oxidation-Reduction, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Protein Binding, Protein Transport, Ubiquitin, biology, Chemistry, 3. Good health, Cell biology, Mitochondrial respiratory chain, RESA1, Molecular Medicine, Intermembrane space, Research Article, Mitochondrial DNA, Mitochondrial disease, COA7, 03 medical and health sciences, medicine, Cytochrome c oxidase, Pharmacology & Drug Discovery, medicine.disease, 030104 developmental biology, biology.protein, Genetics, Gene Therapy & Genetic Disease, 030217 neurology & neurosurgery
Abstract: Nuclear and mitochondrial genome mutations lead to various mitochondrial diseases, many of which affect the mitochondrial respiratory chain. The proteome of the intermembrane space (IMS) of mitochondria consists of several important assembly factors that participate in the biogenesis of mitochondrial respiratory chain complexes. The present study comprehensively analyzed a recently identified IMS protein cytochrome c oxidase assembly factor 7 (COA7), or RESpiratory chain Assembly 1 (RESA1) factor that is associated with a rare form of mitochondrial leukoencephalopathy and complex IV deficiency. We found that COA7 requires the mitochondrial IMS import and assembly (MIA) pathway for efficient accumulation in the IMS. We also found that pathogenic mutant versions of COA7 are imported slower than the wild‐type protein, and mislocalized proteins are degraded in the cytosol by the proteasome. Interestingly, proteasome inhibition rescued both the mitochondrial localization of COA7 and complex IV activity in patient‐derived fibroblasts. We propose proteasome inhibition as a novel therapeutic approach for a broad range of mitochondrial pathologies associated with the decreased levels of mitochondrial proteins. peerReviewed
Published: 2019

28. Structural rather than catalytic role for mitochondrial respiratory chain supercomplexes

Author: Michele Brischigliaro, Alfredo Cabrera-Orefice, Susanne Arnold, Carlo Viscomi, Massimo Zeviani, and Erika Fernández-Vizarra
Subjects: Mitochondria, OXPHOS, supercomplexes, Drosophila, Medicine, Science, Biology (General), QH301-705.5
Abstract: Mammalian mitochondrial respiratory chain (MRC) complexes are able to associate into quaternary structures named supercomplexes (SCs), which normally coexist with non-bound individual complexes. The functional significance of SCs has not been fully clarified and the debate has been centered on whether or not they confer catalytic advantages compared with the non-bound individual complexes. Mitochondrial respiratory chain organization does not seem to be conserved in all organisms. In fact, and differently from mammalian species, mitochondria from Drosophila melanogaster tissues are characterized by low amounts of SCs, despite the high metabolic demands and MRC activity shown by these mitochondria. Here, we show that attenuating the biogenesis of individual respiratory chain complexes was accompanied by increased formation of stable SCs, which are missing in Drosophila melanogaster in physiological conditions. This phenomenon was not accompanied by an increase in mitochondrial respiratory activity. Therefore, we conclude that SC formation is necessary to stabilize the complexes in suboptimal biogenesis conditions, but not for the enhancement of respiratory chain catalysis.
Published: 2023
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29. MR-1S Interacts with PET100 and PET117 in Module-Based Assembly of Human Cytochrome c Oxidase

Author: Sergio Guerrero-Castillo, Shujing Ding, Susanne Arnold, Valeria Tiranti, Michael E. Harbour, Massimo Zeviani, Erika Fernandez-Vizarra, Ian M. Fearnley, Alba Signes, Robert W. Taylor, and Sara Vidoni
Subjects: 0301 basic medicine, Cytochrome, Mutant, Muscle Proteins, COX assembly, SILAC, PET117, MR-1S, Stable isotope labeling by amino acids in cell culture, cytochrome c oxidase, lcsh:QH301-705.5, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Cells, Cultured, Oxidase test, Tumor, Cultured, biology, complexome profiling, Adaptor Proteins, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Cell biology, Mitochondrial, Mitochondria, Mitochondrial respiratory chain, Gene isoform, Cells, mitochondrial respiratory chain, DNA, Mitochondrial, General Biochemistry, Genetics and Molecular Biology, Cell Line, Electron Transport Complex IV, Mitochondrial Proteins, 03 medical and health sciences, Cell Line, Tumor, PET100, Cytochrome c oxidase, myofibrillogenesis regulator 1 short isoform, Adaptor Proteins, Signal Transducing, Cell Nucleus, Humans, Molecular Chaperones, Protein Subunits, Signal Transducing, DNA, Molecular biology, 030104 developmental biology, lcsh:Biology (General), biology.protein, Biogenesis
Abstract: The biogenesis of human cytochrome c oxidase (COX) is an intricate process in which three mitochondrial DNA (mtDNA)-encoded core subunits are assembled in a coordinated way with at least 11 nucleus-encoded subunits. Many chaperones shared between yeast and humans are involved in COX assembly. Here, we have used a MT-CO3 mutant cybrid cell line to define the composition of assembly intermediates and identify new human COX assembly factors. Quantitative mass spectrometry analysis led us to modify the assembly model from a sequential pathway to a module-based process. Each module contains one of the three core subunits, together with different ancillary components, including HIGD1A. By the same analysis, we identified the short isoform of the myofibrillogenesis regulator 1 (MR-1S) as a new COX assembly factor, which works with the highly conserved PET100 and PET117 chaperones to assist COX biogenesis in higher eukaryotes.
Published: 2017

30. TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III

Author: Raffaele Cerutti, Carla Giordano, Sabrina Ravaglia, Giulia d'Amati, Erika Fernandez-Vizarra, Massimo Zeviani, Carlo Viscomi, Sukru Anil Dogan, Ian M. Fearnley, Michael E. Harbour, and Emanuela Bottani
Subjects: 0301 basic medicine, Iron-Sulfur Proteins, Male, Mitochondrial Diseases, Dimer, Inbred C57BL, Nervous System, chemistry.chemical_compound, Electron Transport Complex III, Mice, complex III deficiency, mitochondrial complex III, mitochondrial disease, mitochondrial quality control, mitochondrial respiratory chain, mouse model, Rieske protein, TTC19, UQCRFS1, Animals, Behavior, Animal, Disease Models, Animal, Female, Genotype, HeLa Cells, Humans, Kinetics, Membrane Proteins, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Mitochondrial Proteins, Motor Activity, Nerve Degeneration, Phenotype, Protein Binding, Protein Stability, Proteolysis, Reactive Oxygen Species, Respiratory system, chemistry.chemical_classification, biology, Biochemistry, Knockout, 03 medical and health sciences, Molecular Biology, Reactive oxygen species, Behavior, Animal, Cell Biology, Mitochondrial respiratory chain complex III, 030104 developmental biology, chemistry, Coenzyme Q – cytochrome c reductase, Disease Models, biology.protein, rieske protein, Biogenesis
Abstract: Loss-of-function mutations in TTC19 (tetra-tricopeptide repeat domain 19) have been associated with severe neurological phenotypes and mitochondrial respiratory chain complex III deficiency. We previously demonstrated the mitochondrial localization of TTC19 and its link with complex III biogenesis. Here we provide detailed insight into the mechanistic role of TTC19, by investigating a Ttc19?/? mouse model that shows progressive neurological and metabolic decline, decreased complex III activity, and increased production of reactive oxygen species. By using both the Ttc19?/? mouse model and a range of human cell lines, we demonstrate that TTC19 binds to the fully assembled complex III dimer, i.e., after the incorporation of the iron-sulfur Rieske protein (UQCRFS1). The in situ maturation of UQCRFS1 produces N-terminal polypeptides, which remain bound to holocomplex III. We show that, in normal conditions, these UQCRFS1 fragments are rapidly removed, but when TTC19 is absent they accumulate within complex III, causing its structural and functional impairment.
Published: 2017

31. Mutations in APOPT1, Encoding a Mitochondria! Protein, Cause Cavitating Leukoencephalopathy with Cytochrome c Oxidase Deficiency

Author: Daniele Ghezzi, Isabella Moroni, Anna Ardissone, Marjo S. van der Knaap, Alessandra Torraco, René Stevens, Thomas Meitinger, Holger Prokisch, Graziella Uziel, Pinar Tekturk, Zuhal Yapici, Costanza Lamperti, Tobias B. Haack, Daria Diodato, Enrico Bertini, Truus E.M. Abbink, Silvia Marchet, Fathiya Al-Murshedi, Robert W. Taylor, Rosalba Carrozzo, Erika Fernandez-Vizarra, Steven A. Hardy, Massimo Zeviani, Tim M. Strom, Richard J. Rodenburg, Laura Melchionda, Maurizio Moggio, Eleonora Lamantea, Lucia Morandi, Functional Genomics, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Pediatric surgery, and NCA - Brain mechanisms in health and disease
Subjects: Adult, Male, Adolescent, Cells, Mitochondrial disease, Mutant, Cytochrome-c Oxidase Deficiency, Oxidative phosphorylation, Mitochondrion, medicine.disease_cause, Electron Transport Complex IV, Mitochondrial Proteins, Myoblasts, SDG 3 - Good Health and Well-being, Leukoencephalopathies, Report, Complementary DNA, Apoptosis Regulatory Proteins, Cells, Cultured, Child, Child, Preschool, Female, Fibroblasts, Humans, Infant, Magnetic Resonance Imaging, Mitochondria, Mutation, Genetics, medicine, Cytochrome c oxidase, Genetics(clinical), Preschool, Genetics (clinical), Gene knockdown, Cultured, biology, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], medicine.disease, Molecular biology, biology.protein
Abstract: Contains fulltext : 137503.pdf (Publisher’s version ) (Open Access) Cytochrome c oxidase (COX) deficiency is a frequent biochemical abnormality in mitochondrial disorders, but a large fraction of cases remains genetically undetermined. Whole-exome sequencing led to the identification of APOPT1 mutations in two Italian sisters and in a third Turkish individual presenting severe COX deficiency. All three subjects presented a distinctive brain MRI pattern characterized by cavitating leukodystrophy, predominantly in the posterior region of the cerebral hemispheres. We then found APOPT1 mutations in three additional unrelated children, selected on the basis of these particular MRI features. All identified mutations predicted the synthesis of severely damaged protein variants. The clinical features of the six subjects varied widely from acute neurometabolic decompensation in late infancy to subtle neurological signs, which appeared in adolescence; all presented a chronic, long-surviving clinical course. We showed that APOPT1 is targeted to and localized within mitochondria by an N-terminal mitochondrial targeting sequence that is eventually cleaved off from the mature protein. We then showed that APOPT1 is virtually absent in fibroblasts cultured in standard conditions, but its levels increase by inhibiting the proteasome or after oxidative challenge. Mutant fibroblasts showed reduced amount of COX holocomplex and higher levels of reactive oxygen species, which both shifted toward control values by expressing a recombinant, wild-type APOPT1 cDNA. The shRNA-mediated knockdown of APOPT1 in myoblasts and fibroblasts caused dramatic decrease in cell viability. APOPT1 mutations are responsible for infantile or childhood-onset mitochondrial disease, hallmarked by the combination of profound COX deficiency with a distinctive neuroimaging presentation.
Published: 2014

32. MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion

Author: Vamsi K. Mootha, Pietro Strisciuglio, Emmanuelle Sarzi, Claudia Donnini, Massimo Zeviani, Sarah E. Calvo, Valeria Tiranti, Antonella Spinazzola, Erika Fernandez-Vizarra, Agnès Rötig, Carlo Viscomi, Pio D'Adamo, Salvatore DiMauro, René Massimiliano Marsano, Alicia Chan, Iliana Ferrero, Rossella Parini, Hans Weiher, Franco Carrara, Paolo Gasparini, Spinazzola, A, Viscomi, C, FERNANDEZ VIZARRA, E, Carrara, F, D'Adamo, ADAMO PIO, Calvo, S, Marsano, Rm, Donnini, C, Weiher, H, Strisciuglio, P, Parini, R, Sarzi, E, Chan, A, Dimauro, S, Rtig, A, Gasparini, Paolo, Ferrero, I, Mootha, Vk, Tiranti, V, Zeviani, M., Antonella, Spinazzola, Carlo, Viscomi, Erika Fernandez, Vizarra, Franco, Carrara, Pio, D'Adamo, Sarah, Calvo, René Massimiliano, Marsano, Claudia, Donnini, Hans, Weiher, Strisciuglio, Pietro, Rossella, Parini, Emmanuelle, Sarzi, Alicia, Chan, Salvatore, Dimauro, Agnes, Rötig, Paolo, Gasparini, Iliana, Ferrero, Vamsi K., Mootha, Valeria, Tiranti, and Massimo, Zeviani
Subjects: Male, MPV17, Mitochondrial DNA, SUCLA2, Cells, Molecular Sequence Data, Fluorescent Antibody Technique, Mitochondrion, Biology, DGUOK, DNA, Mitochondrial, Mitochondrial depletion, Chromosomes, Mice, Genetics, medicine, Amino Acid Sequence, Animals, Cells, Cultured, Chromosomes, Human, Pair 2, Cloning, Molecular, Female, Humans, Intracellular Membranes, Liver Diseases, Membrane Proteins, Mitochondria, Pedigree, Syndrome, Mutation, infantile hepatic mitochondrial DNA depletion, Inner mitochondrial membrane, Cultured, Molecular, DNA, medicine.disease, Molecular biology, Mitochondrial, Pair 2, Mitochondrial DNA depletion syndrome, mitochondrial (mt) DNA depletion syndromes, Human, Cloning
Abstract: The mitochondrial (mt) DNA depletion syndromes (MDDS) are genetic disorders characterized by a severe, tissue-specific decrease of mtDNA copy number, leading to organ failure. There are two main clinical presentations: myopathic (OMIM 609560) and hepatocerebral1 (OMIM 251880). Known mutant genes, including TK2 (ref. 2), SUCLA2 (ref. 3), DGUOK (ref. 4) and POLG5,6, account for only a fraction of MDDS cases7. We found a new locus for hepatocerebral MDDS on chromosome 2p21-23 and prioritized the genes on this locus using a new integrative genomics strategy. One of the top-scoring candidates was the human ortholog of the mouse kidney disease gene Mpv17 (ref. 8). We found disease-segregating mutations in three families with hepatocerebral MDDS and demonstrated that, contrary to the alleged peroxisomal localization of the MPV17 gene product9, MPV17 is a mitochondrial inner membrane protein, and its absence or malfunction causes oxidative phosphorylation (OXPHOS) failure and mtDNA depletion, not only in affected individuals but also in Mpv17 –/– mice.
Published: 2006

33. LYRM7/MZM1L is a UQCRFS1 chaperone involved in the last steps of mitochondrial Complex III assembly in human cells

Author: Dennis R. Winge, Jennifer L. Fox, Teresa Lobo, Ester Sánchez, Erika Fernandez-Vizarra, and Massimo Zeviani
Subjects: Iron-Sulfur Proteins, Mitochondrial respiratory chain, Saccharomyces cerevisiae Proteins, Protein subunit, Complex III, Saccharomyces cerevisiae, Molecular Sequence Data, Biophysics, Biology, Biochemistry, Article, Mitochondrial Proteins, 03 medical and health sciences, Electron Transport Complex III, Mice, 0302 clinical medicine, Animals, Humans, Amino Acid Sequence, Inner mitochondrial membrane, 030304 developmental biology, Assembly factor, chemistry.chemical_classification, 0303 health sciences, ATPases Associated with Diverse Cellular Activities, Apoptosis Regulatory Proteins, HEK293 Cells, HeLa Cells, Molecular Chaperones, Cell Biology, biology.organism_classification, Enzyme, chemistry, Mitochondrial matrix, Chaperone (protein), Coenzyme Q – cytochrome c reductase, biology.protein, lipids (amino acids, peptides, and proteins), 030217 neurology & neurosurgery
Abstract: The mammalian Complex III (CIII) assembly process is yet to be completely understood. There is still a lack in understanding of how the structural subunits are put together and which additional factors are involved. Here we describe the identification and characterization of LYRM7, a human protein displaying high sequence homology to the Saccharomyces cerevisiae protein Mzm1, which was recently shown as an assembly factor for Rieske Fe–S protein incorporation into the yeast cytochrome bc1 complex. We conclude that human LYRM7, which we propose to be renamed MZM1L (MZM1-like), works as a human Rieske Fe–S protein (UQCRFS1) chaperone, binding to this subunit within the mitochondrial matrix and stabilizing it prior to its translocation and insertion into the late CIII dimeric intermediate within the mitochondrial inner membrane. Thus, LYRM7/MZM1L is a novel human CIII assembly factor involved in the UQCRFS1 insertion step, which enables formation of the mature and functional CIII enzyme.
Published: 2013

34. Supercomplex assembly determines electron flux in the mitochondrial electron transport chain

Author: Acisclo Pérez-Martos, Raquel Moreno-Loshuertos, Pedro M. Quirós, Raquel Cruz, M. A. C. Rodríguez-Hernández, Enrique Calvo, José Antonio Enríquez, Angel Carracedo, Plácido Navas, Carmen Colás, Erika Fernandez-Vizarra, Esther Lapuente-Brun, Ana Latorre-Pellicer, Carlos López-Otín, Eduardo Balsa, Ester Perales-Clemente, Patricio Fernández-Silva, and Rebeca Acín-Pérez
Subjects: Stereochemistry, Ubiquinone, Cells, Molecular Sequence Data, Biology, Inbred C57BL, Electron Transport, Electron Transport Complex IV, Electron Transport Complex III, Mice, Amino Acid Sequence, Animals, Cells, Cultured, Cytochromes c, Electron Transport Complex I, Gene Knockdown Techniques, HEK293 Cells, Humans, Mice, Inbred C57BL, Mitochondria, Multidisciplinary, Cultured, Cytochrome c, Genetic modulation, Electron transport chain, Crystallography, Electron flux, Coenzyme Q – cytochrome c reductase, Respirasome, biology.protein
Abstract: Report.-- et al., The textbook description of mitochondrial respiratory complexes (RCs) views them as free-moving entities linked by the mobile carriers coenzyme Q (CoQ) and cytochrome c (cyt c). This model (known as the fluid model) is challenged by the proposal that all RCs except complex II can associate in supercomplexes (SCs). The proposed SCs are the respirasome (complexes I, III, and IV), complexes I and III, and complexes III and IV. The role of SCs is unclear, and their existence is debated. By genetic modulation of interactions between complexes I and III and III and IV, we show that these associations define dedicated CoQ and cyt c pools and that SC assembly is dynamic and organizes electron flux to optimize the use of available substrates.
Published: 2013

35. Mitochondrial Cytochrome c Oxidase Defects Alter Cellular Homeostasis of Transition Metals

Author: Michele Brischigliaro, Denis Badocco, Rodolfo Costa, Carlo Viscomi, Massimo Zeviani, Paolo Pastore, and Erika Fernández-Vizarra
Subjects: mitochondrial respiratory chain, cytochrome c oxidase, copper, iron, zinc, manganese, Biology (General), QH301-705.5
Abstract: The redox activity of cytochrome c oxidase (COX), the terminal oxidase of the mitochondrial respiratory chain (MRC), depends on the incorporation of iron and copper into its catalytic centers. Many mitochondrial proteins have specific roles for the synthesis and delivery of metal-containing cofactors during COX biogenesis. In addition, a large set of different factors possess other molecular functions as chaperones or translocators that are also necessary for the correct maturation of these complexes. Pathological variants in genes encoding structural MRC subunits and these different assembly factors produce respiratory chain deficiency and lead to mitochondrial disease. COX deficiency in Drosophila melanogaster, induced by downregulated expression of three different assembly factors and one structural subunit, resulted in decreased copper content in the mitochondria accompanied by different degrees of increase in the cytosol. The disturbances in metal homeostasis were not limited only to copper, as some changes in the levels of cytosolic and/or mitochondrial iron, manganase and, especially, zinc were observed in several of the COX-deficient groups. The altered copper and zinc handling in the COX defective models resulted in a transcriptional response decreasing the expression of copper transporters and increasing the expression of metallothioneins. We conclude that COX deficiency is generally responsible for an altered mitochondrial and cellular homeostasis of transition metals, with variations depending on the origin of COX assembly defect.
Published: 2022
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36. Editorial: Mitochondrial OXPHOS System: Emerging Concepts and Technologies and Role in Disease

Author: Erika Fernández-Vizarra, Sylvie Callegari, Glòria Garrabou, and David Pacheu-Grau
Subjects: mitochondria, OXPHOS, mtDNA, mitochondrial proteome, mitochondrial dysfunction, mitochondrial quality control, Biology (General), QH301-705.5
Published: 2022
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37. Isolation of mitochondria for biogenetical studies: An update

Author: Erika Fernandez-Vizarra, José Antonio Enríquez, Acisclo Pérez-Martos, Massimo Zeviani, Patricio Fernández-Silva, and Gustavo Ferrín
Subjects: Mitochondrial DNA, Isolation of mitochondria, In organello assays, mtDNA expression studies, Protein import, Animals, Cell Fractionation, Mice, Mitochondria, Rats, Aminoacylation, Mitochondrion, Biology, chemistry.chemical_compound, Organelle, Protein biosynthesis, Molecular Biology, RNA, MtDNA expression studies, Cell Biology, Cell biology, Biochemistry, chemistry, Molecular Medicine, Biogenesis, DNA
Abstract: The use of good quality preparations of isolated mitochondria is necessary when studying the mitochondrial biogenetical activities. This article explains a fast and simple method for the purification of mammalian mitochondria from different tissues and cultured cells, that is suitable for the analysis of many aspects of the organelle’s biogenesis. The mitochondria isolated following the protocol described here, are highly active and capable of DNA, RNA and protein synthesis. Mitochondrial tRNA aminoacylation, mtDNA–protein interactions and specific import of added proteins into the organelles, can also be studied using this kind of preparations.
Published: 2010

38. Five entry points of the mitochondrially encoded subunits in mammalian complex I assembly

Author: Nieves Movilla, Rebeca Acín-Pérez, Raquel Moreno-Loshuertos, María Pilar Bayona-Bafaluy, José Antonio Enríquez, Acisclo Pérez-Martos, Patricio Fernández-Silva, Erika Fernandez-Vizarra, and Ester Perales-Clemente
Subjects: Electrophoresis, Mitochondrial DNA, Protein subunit, DNA Mutational Analysis, Molecular Sequence Data, Mitochondrion, Biology, medicine.disease_cause, MT-RNR1, DNA, Mitochondrial, Models, Biological, Cell Line, Mice, Models, medicine, Animals, Molecular Biology, Base Sequence, Electron Transport Complex I, Electrophoresis, Polyacrylamide Gel, Mitochondria, Mutation, Nuclear Proteins, Protein Subunits, Staining and Labeling, Genetics, Polyacrylamide Gel, Cell Biology, Articles, DNA, Biological, Cell biology, Mitochondrial, Mitochondrial respiratory chain, Biogenesis
Abstract: Complex I (CI) is the largest enzyme of the mammalian mitochondrial respiratory chain. The biogenesis of the complex is a very complex process due to its large size and number of subunits (45 subunits). The situation is further complicated due to the fact that its subunits have a double genomic origin, as seven of them are encoded by the mitochondrial DNA. Understanding of the assembly process and characterization of the involved factors has advanced very much in the last years. However, until now, a key part of the process, that is, how and at which step the mitochondrially encoded CI subunits (ND subunits) are incorporated in the CI assembly process, was not known. Analyses of several mouse cell lines mutated for three ND subunits allowed us to determine the importance of each one for complex assembly/stability and that there are five different steps within the assembly pathway in which some mitochondrially encoded CI subunit is incorporated.
Published: 2010

39. Early-onset liver mtDNA depletion and late-onset proteinuric nephropathy in Mpv17 knockout mice

Author: Marina Mora, Erika Fernandez-Vizarra, Roberto Vettor, Carlo Viscomi, Massimo Zeviani, Marco Maggioni, Claudio Pagano, Valeria Massa, and Antonella Spinazzola
Subjects: medicine.medical_specialty, Cirrhosis, Transcription, Genetic, Cells, Knockout, Respiratory chain, Biology, DNA, Mitochondrial, Mitochondrial depletion, Nephropathy, Focal Segmental, Mitochondrial Proteins, Mice, Focal segmental glomerulosclerosis, Glomerulosclerosis, Genetic, Internal medicine, Genetics, medicine, Animals, Humans, Age of Onset, MPV17, Molecular Biology, Cells, Cultured, Genetics (clinical), Mice, Knockout, Cultured, Glomerulosclerosis, Focal Segmental, Animal, Disease Models, Animal, Fibroblasts, Liver, Membrane Proteins, Organ Specificity, Proteinuria, Transcription Factors, Articles, General Medicine, Anatomy, DNA, medicine.disease, Mitochondrial, Endocrinology, Knockout mouse, Disease Models, Transcription
Abstract: In humans, MPV17 mutations are responsible for severe mitochondrial depletion syndrome, mainly affecting the liver and the nervous system. To gain insight into physiopathology of MPV17-related disease, we investigated an available Mpv17 knockout animal model. We found severe mtDNA depletion in liver and, albeit to a lesser extent, in skeletal muscle, whereas hardly any depletion was detected in brain and kidney, up to 1 year after birth. Mouse embryonic fibroblasts did show mtDNA depletion, but only after several culturing passages, or in a serumless culturing medium. In spite of severe mtDNA depletion, only moderate decrease in respiratory chain enzymatic activities, and mild cytoarchitectural alterations, were observed in the Mpv17(-/-) livers, but neither cirrhosis nor failure ever occurred in this organ at any age. The mtDNA transcription rate was markedly increased in liver, which could contribute to compensate the severe mtDNA depletion. This phenomenon was associated with specific downregulation of Mterf1, a negative modulator of mtDNA transcription. The most relevant clinical features involved skin, inner ear and kidney. The coat of the Mpv17(-/-) mice turned gray early in adulthood, and 18-month or older mice developed focal segmental glomerulosclerosis (FSGS) with massive proteinuria. Concomitant degeneration of cochlear sensory epithelia was reported as well. These symptoms were associated with significantly shorter lifespan. Coincidental with the onset of FSGS, there was hardly any mtDNA left in the glomerular tufts. These results demonstrate that Mpv17 controls mtDNA copy number by a highly tissue- and possibly cytotype-specific mechanism.
Published: 2009

40. FASTKD2 nonsense mutation in an infantile mitochondrial encephalomyopathy associated with cytochrome c oxidase deficiency

Author: Orly Elpeleg, Pio D'Adamo, Paolo Gasparini, Daniele Ghezzi, Massimo Zeviani, Valeria Tiranti, Erika Fernandez-Vizarra, Ann Saada, Ghezzi, D, Saada, A, D'Adamo, ADAMO PIO, FERNANDEZ VIZARRA, E, Gasparini, Paolo, Tiranti, V, Elpeleg, O, and Zeviani, M.
Subjects: Mitochondrial encephalomyopathy, Male, Candidate gene, Mutant, Nonsense mutation, Cytochrome-c Oxidase Deficiency, Mitochondrion, Protein Serine-Threonine Kinases, Mitochondrial myopathy, Mitochondrial Encephalomyopathies, Report, Chlorocebus aethiops, medicine, Genetics, Cytochrome c oxidase, Animals, Humans, Genetics(clinical), Genetic Predisposition to Disease, COS Cells, Female, HeLa Cells, Infant, Infant, Newborn, Mitochondria, Muscle, Skeletal, Pedigree, Protein-Serine-Threonine Kinases, Siblings, Codon, Nonsense, Codon, Genetics (clinical), biology, Skeletal, medicine.disease, Newborn, Nonsense, biology.protein, Muscle
Abstract: In two siblings we found a mitochondrial encephalomyopathy, characterized by developmental delay, hemiplegia, convulsions, asymmetrical brain atrophy, and low cytochrome c oxidase (COX) activity in skeletal muscle. The disease locus was identified on chromosome 2 by homozygosity mapping; candidate genes were prioritized for their known or predicted mitochondrial localization and then sequenced in probands and controls. A homozygous nonsense mutation in the KIAA0971 gene segregated with the disease in the proband family. The corresponding protein is known as fas activated serine-threonine kinase domain 2, FASTKD2. Confocal immunofluorescence colocalized a tagged recombinant FASTKD2 protein with mitochondrial markers, and membrane-potential-dependent in vitro mitochondrial import was demonstrated in isolated mitochondria. In staurosporine-induced-apoptosis experiments, decreased nuclear fragmentation was detected in treated mutant versus control fibroblasts. In conclusion, we found a loss-of-function mutation in a gene segregating with a peculiar mitochondrial encephalomyopathy associated with COX deficiency in skeletal muscle. The corresponding protein is localized in the mitochondrial inner compartment. Preliminary data indicate that FASTKD2 plays a role in mitochondrial apoptosis.
Published: 2008

41. Severe infantile encephalomyopathy caused by a mutation in COX6B1, a nucleus-encoded subunit of cytochrome c oxidase

Author: Erika Fernandez-Vizarra, Massimo Zeviani, Pio D'Adamo, Saad Alshahwan, Eman Bakhsh, Paola Goffrini, Valeria Massa, Ileana Ferrero, Paolo Gasparini, Paolo Mereghetti, V., Massa, E., Fernandez Vizarra, S., Alshahwan, E., Bakhsh, P., Goffrini, I., Ferrero, P., Mereghetti, D'Adamo, ADAMO PIO, Gasparini, Paolo, and M., Zeviani
Subjects: Models, Molecular, Male, Protein Conformation, Cytochrome-c Oxidase Deficiency, Sequence Homology, medicine.disease_cause, Models, Genetics(clinical), Child, Genetics (clinical), Genetics, Mutation, Brain Diseases, biology, Encephalomyopathy, pediatrics, Brain, Magnetic Resonance Imaging, Pedigree, Amino Acid, medicine.anatomical_structure, Female, RNA Interference, Mitochondrial DNA, Protein subunit, Molecular Sequence Data, Article, Electron Transport Complex IV, medicine, Cytochrome c oxidase, Humans, Point Mutation, Amino Acid Sequence, Amino Acid Substitution, Base Sequence, Brain Diseases, Metabolic, Inborn, Cell Nucleus, Genetic Complementation Test, Haplotypes, HeLa Cells, Infant, Sequence Homology, Amino Acid, Gene, Point mutation, Haplotype, Molecular, Cell nucleus, Inborn, biology.protein, Metabolic
Abstract: Cytochrome c oxidase (COX) deficiency, one of the most common respiratory-chain defects in humans, has been associated with mutations in either mitochondrial DNA genes or nucleus-encoded proteins that are not part in but promote the biogenesis of COX. Mutations of nucleus-encoded structural subunits were sought for but never found in COX-defective patients, leading to the conjecture that they may be incompatible with extra-uterine survival. We report a disease-associated mutation in one such subunit, COX6B1. Nuclear-encoded COX genes should be reconsidered and included in the diagnostic mutational screening of human disorders related to COX deficiency.
Published: 2008

42. Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu

Author: Claudio Castellan, Valeria Tiranti, Erika Fernandez-Vizarra, Lucia Valente, Paolo Mereghetti, Massimo Zeviani, Luca De Gioia, René Massimiliano Marsano, Salvatore Savasta, Giacomo P. Comi, Edoardo Malfatti, Alberto Burlina, Iliana Ferrero, and Claudia Donnini
Subjects: Models, Molecular, Mitochondrial DNA, Mitochondrial translation, Mitochondrial disease, Cells, Molecular Sequence Data, Saccharomyces cerevisiae, Mitochondrion, Biology, Peptide Elongation Factor Tu, DNA, Mitochondrial, Human mitochondrial genetics, Amino Acid Sequence, Antigens, Neoplasm, Brain, Cells, Cultured, Child, Preschool, Female, Fibroblasts, Humans, Infant, Infant, Newborn, Mitochondrial Encephalomyopathies, Mitochondrial Proteins, Mutation, Peptide Elongation Factor G, Article, Models, medicine, Genetics, Genetics(clinical), Antigens, Child, Preschool, Genetics (clinical), Cultured, Molecular, DNA, medicine.disease, Newborn, Mitochondrial, mitochondrial fusion, DNAJA3, Neoplasm
Abstract: Mitochondrial protein translation is a complex process performed within mitochondria by an apparatus composed of mitochondrial DNA (mtDNA)–encoded RNAs and nuclear DNA–encoded proteins. Although the latter by far outnumber the former, the vast majority of mitochondrial translation defects in humans have been associated with mutations in RNA-encoding mtDNA genes, whereas mutations in protein-encoding nuclear genes have been identified in a handful of cases. Genetic investigation involving patients with defective mitochondrial translation led us to the discovery of novel mutations in the mitochondrial elongation factor G1 (EFG1) in one affected baby and, for the first time, in the mitochondrial elongation factor Tu (EFTu) in another one. Both patients were affected by severe lactic acidosis and rapidly progressive, fatal encephalopathy. The EFG1-mutant patient had early-onset Leigh syndrome, whereas the EFTu-mutant patient had severe infantile macrocystic leukodystrophy with micropolygyria. Structural modeling enabled us to make predictions about the effects of the mutations at the molecular level. Yeast and mammalian cell systems proved the pathogenic role of the mutant alleles by functional complementation in vivo. Nuclear-gene abnormalities causing mitochondrial translation defects represent a new, potentially broad field of mitochondrial medicine. Investigation of these defects is important to expand the molecular characterization of mitochondrial disorders and also may contribute to the elucidation of the complex control mechanisms, which regulate this fundamental pathway of mtDNA homeostasis.
Published: 2007

43. Redox-Mediated Regulation of Mitochondrial Biogenesis, Dynamics, and Respiratory Chain Assembly in Yeast and Human Cells

Author: Stefan Geldon, Erika Fernández-Vizarra, and Kostas Tokatlidis
Subjects: mitochondria, biogenesis, protein import, redox signaling, ROS, respiratory chain assembly, Biology (General), QH301-705.5
Abstract: Mitochondria are double-membrane organelles that contain their own genome, the mitochondrial DNA (mtDNA), and reminiscent of its endosymbiotic origin. Mitochondria are responsible for cellular respiration via the function of the electron oxidative phosphorylation system (OXPHOS), located in the mitochondrial inner membrane and composed of the four electron transport chain (ETC) enzymes (complexes I-IV), and the ATP synthase (complex V). Even though the mtDNA encodes essential OXPHOS components, the large majority of the structural subunits and additional biogenetical factors (more than seventy proteins) are encoded in the nucleus and translated in the cytoplasm. To incorporate these proteins and the rest of the mitochondrial proteome, mitochondria have evolved varied, and sophisticated import machineries that specifically target proteins to the different compartments defined by the two membranes. The intermembrane space (IMS) contains a high number of cysteine-rich proteins, which are mostly imported via the MIA40 oxidative folding system, dependent on the reduction, and oxidation of key Cys residues. Several of these proteins are structural components or assembly factors necessary for the correct maturation and function of the ETC complexes. Interestingly, many of these proteins are involved in the metalation of the active redox centers of complex IV, the terminal oxidase of the mitochondrial ETC. Due to their function in oxygen reduction, mitochondria are the main generators of reactive oxygen species (ROS), on both sides of the inner membrane, i.e., in the matrix and the IMS. ROS generation is important due to their role as signaling molecules, but an excessive production is detrimental due to unwanted oxidation reactions that impact on the function of different types of biomolecules contained in mitochondria. Therefore, the maintenance of the redox balance in the IMS is essential for mitochondrial function. In this review, we will discuss the role that redox regulation plays in the maintenance of IMS homeostasis as well as how mitochondrial ROS generation may be a key regulatory factor for ETC biogenesis, especially for complex IV.
Published: 2021
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44. Loss of COX4I1 Leads to Combined Respiratory Chain Deficiency and Impaired Mitochondrial Protein Synthesis

Author: Kristýna Čunátová, David Pajuelo Reguera, Marek Vrbacký, Erika Fernández-Vizarra, Shujing Ding, Ian M. Fearnley, Massimo Zeviani, Josef Houštěk, Tomáš Mráček, and Petr Pecina
Subjects: mitochondria, OXPHOS, cI, COX, cIV, COX4, Cytology, QH573-671
Abstract: The oxidative phosphorylation (OXPHOS) system localized in the inner mitochondrial membrane secures production of the majority of ATP in mammalian organisms. Individual OXPHOS complexes form supramolecular assemblies termed supercomplexes. The complexes are linked not only by their function but also by interdependency of individual complex biogenesis or maintenance. For instance, cytochrome c oxidase (cIV) or cytochrome bc1 complex (cIII) deficiencies affect the level of fully assembled NADH dehydrogenase (cI) in monomeric as well as supercomplex forms. It was hypothesized that cI is affected at the level of enzyme assembly as well as at the level of cI stability and maintenance. However, the true nature of interdependency between cI and cIV is not fully understood yet. We used a HEK293 cellular model where the COX4 subunit was completely knocked out, serving as an ideal system to study interdependency of cI and cIV, as early phases of cIV assembly process were disrupted. Total absence of cIV was accompanied by profound deficiency of cI, documented by decrease in the levels of cI subunits and significantly reduced amount of assembled cI. Supercomplexes assembled from cI, cIII, and cIV were missing in COX4I1 knock-out (KO) due to loss of cIV and decrease in cI amount. Pulse-chase metabolic labeling of mitochondrial DNA (mtDNA)-encoded proteins uncovered a decrease in the translation of cIV and cI subunits. Moreover, partial impairment of mitochondrial protein synthesis correlated with decreased content of mitochondrial ribosomal proteins. In addition, complexome profiling revealed accumulation of cI assembly intermediates, indicating that cI biogenesis, rather than stability, was affected. We propose that attenuation of mitochondrial protein synthesis caused by cIV deficiency represents one of the mechanisms, which may impair biogenesis of cI.
Published: 2021
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45. COX7A2L Is a Mitochondrial Complex III Binding Protein that Stabilizes the III2+IV Supercomplex without Affecting Respirasome Formation

Author: Rafael Pérez-Pérez, Teresa Lobo-Jarne, Dusanka Milenkovic, Arnaud Mourier, Ana Bratic, Alberto García-Bartolomé, Erika Fernández-Vizarra, Susana Cadenas, Aitor Delmiro, Inés García-Consuegra, Joaquín Arenas, Miguel A. Martín, Nils-Göran Larsson, and Cristina Ugalde
Subjects: Biology (General), QH301-705.5
Abstract: Mitochondrial respiratory chain (MRC) complexes I, III, and IV associate into a variety of supramolecular structures known as supercomplexes and respirasomes. While COX7A2L was originally described as a supercomplex-specific factor responsible for the dynamic association of complex IV into these structures to adapt MRC function to metabolic variations, this role has been disputed. Here, we further examine the functional significance of COX7A2L in the structural organization of the mammalian respiratory chain. As in the mouse, human COX7A2L binds primarily to free mitochondrial complex III and, to a minor extent, to complex IV to specifically promote the stabilization of the III2+IV supercomplex without affecting respirasome formation. Furthermore, COX7A2L does not affect the biogenesis, stabilization, and function of the individual oxidative phosphorylation complexes. These data show that independent regulatory mechanisms for the biogenesis and turnover of different MRC supercomplex structures co-exist.
Published: 2016
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