27 results on '"Benincá C"'
Search Results
2. Evaluation five years after a Refinary Oil Spill in freshwater wetland - Paraná State, Southern of Brazil
- Author
-
Katsumiti, A., primary, França, P.P., additional, Silva Costa, G.P., additional, Zandoná, E.M., additional, Benincá, C., additional, de Assis, H.C.S., additional, Cestari, M.M., additional, Maschchio, J., additional, Randi, M.A.F., additional, Silva, C.A., additional, Roche, H., additional, and Oliveira-Ribeiro, C.A., additional
- Published
- 2013
- Full Text
- View/download PDF
3. Kinetics of the precipitation reaction between aluminium and contaminant orthophosphate ions.
- Author
-
de Barros IR, Benincá C, and Zanoelo EF
- Subjects
- Kinetics, Hydrogen-Ion Concentration, Wastewater chemistry, Waste Disposal, Fluid methods, Water Purification methods, Phosphates chemistry, Aluminum chemistry, Chemical Precipitation, Water Pollutants, Chemical chemistry, Water Pollutants, Chemical analysis
- Abstract
The removal of phosphorous from wastewater in metal-orthophosphate systems typically occurs by simultaneous adsorption on poorly soluble metal hydroxides and by precipitation reactions between metal ions and orthophosphates in solution. To understand the individual contribution of these mechanisms to the removal of phosphorus, the main aim of this study was to determine the kinetics of consumption of contaminant orthophosphates by the precipitation reaction with aluminium ions in a solution free of insoluble aluminium hydroxide. To define the amount of aluminium and phosphorous compounds to be dissolved in water to have this desired reacting condition at a given pH, the solubilities of KH
2 PO4 (s), Al(OH)3 (s) and AlPO4 (s) were examined at 25 °C in the pH range ∼2.6 to 7.9. pH-solubility diagrams for these ionic solids were made by solving a system of nonlinear algebraic equations involving dissolution, dissociation and hydrolysis reactions at equilibrium. The kinetics of the reaction between aluminium and orthophosphate ions at a reacting condition free of solids except for the product AlPO4 (s) was investigated in a well-stirred batch reactor at pH ∼3.1 and 3.5 at 25 °C. A detailed kinetic model involving ten species, seven reversible reactions of hydrolysis of soluble aluminium and orthophosphate species and one reversible precipitation reaction between aluminium and phosphate ions revealed a rate constant for the latter reaction of 5.968 × 1010 L mol-1 s-1 ( p = 0.191). XRD, TGA/DTGA and EDX analyses of the filtered and dried reacting mixture confirmed that the only solid product of the precipitation reaction was hydrated AlPO4 (s).- Published
- 2024
- Full Text
- View/download PDF
4. Pro-inflammatory macrophage activation does not require inhibition of mitochondrial respiration.
- Author
-
Ball AB, Jones AE, Nguyễn KB, Rios A, Marx N, Hsieh WY, Yang K, Desousa BR, Kim KKO, Veliova M, Del Mundo ZM, Shirihai OS, Benincá C, Stiles L, Bensinger SJ, and Divakaruni AS
- Abstract
Pro-inflammatory macrophage activation is a hallmark example of how mitochondria serve as signaling organelles. Upon classical macrophage activation, oxidative phosphorylation sharply decreases and mitochondria are repurposed to accumulate signals that amplify effector function. However, evidence is conflicting as to whether this collapse in respiration is essential or largely dispensable. Here we systematically examine this question and show that reduced oxidative phosphorylation is not required for pro-inflammatory macrophage activation. Only stimuli that engage both MyD88- and TRIF-linked pathways decrease mitochondrial respiration, and different pro-inflammatory stimuli have varying effects on other bioenergetic parameters. Additionally, pharmacologic and genetic models of electron transport chain inhibition show no direct link between respiration and pro-inflammatory activation. Studies in mouse and human macrophages also reveal accumulation of the signaling metabolites succinate and itaconate can occur independently of characteristic breaks in the TCA cycle. Finally, in vivo activation of peritoneal macrophages further demonstrates that a pro-inflammatory response can be elicited without reductions to oxidative phosphorylation. Taken together, the results suggest the conventional model of mitochondrial reprogramming upon macrophage activation is incomplete.
- Published
- 2024
- Full Text
- View/download PDF
5. The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.
- Author
-
Acevedo A, Jones AE, Danna BT, Turner R, Montales KP, Benincá C, Reue K, Shirihai OS, Stiles L, Wallace M, Wang Y, Bertholet AM, and Divakaruni AS
- Subjects
- Humans, 2,4-Dinitrophenol pharmacology, 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) metabolism, Amino Acids, Branched-Chain metabolism, Animals, Mice, Rats, Cell Line, Cells, Cultured, Lipogenesis drug effects, Metabolic Diseases, Protein Kinase Inhibitors pharmacology, Reactive Oxygen Species metabolism, Mitochondrial Membranes drug effects
- Abstract
Elevated levels of branched chain amino acids (BCAAs) and branched-chain α-ketoacids are associated with cardiovascular and metabolic disease, but the molecular mechanisms underlying a putative causal relationship remain unclear. The branched-chain ketoacid dehydrogenase kinase (BCKDK) inhibitor BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid) is often used in preclinical models to increase BCAA oxidation and restore steady-state BCAA and branched-chain α-ketoacid levels. BT2 administration is protective in various rodent models of heart failure and metabolic disease, but confoundingly, targeted ablation of Bckdk in specific tissues does not reproduce the beneficial effects conferred by pharmacologic inhibition. Here, we demonstrate that BT2, a lipophilic weak acid, can act as a mitochondrial uncoupler. Measurements of oxygen consumption, mitochondrial membrane potential, and patch-clamp electrophysiology show that BT2 increases proton conductance across the mitochondrial inner membrane independently of its inhibitory effect on BCKDK. BT2 is roughly sixfold less potent than the prototypical uncoupler 2,4-dinitrophenol and phenocopies 2,4-dinitrophenol in lowering de novo lipogenesis and mitochondrial superoxide production. The data suggest that the therapeutic efficacy of BT2 may be attributable to the well-documented effects of mitochondrial uncoupling in alleviating cardiovascular and metabolic disease., Competing Interests: Conflict of interest Y. W. is a scientific founder and paid consultant for Ramino Therapeutics. A. S. D. has previously served as a paid consultant for Agilent Technologies., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
6. A mammalian-specific Alex3/Gα q protein complex regulates mitochondrial trafficking, dendritic complexity, and neuronal survival.
- Author
-
Izquierdo-Villalba I, Mirra S, Manso Y, Parcerisas A, Rubio J, Del Valle J, Gil-Bea FJ, Ulloa F, Herrero-Lorenzo M, Verdaguer E, Benincá C, Castro-Torres RD, Rebollo E, Marfany G, Auladell C, Navarro X, Enríquez JA, López de Munain A, Soriano E, and Aragay AM
- Subjects
- Animals, Mice, Mammals metabolism, Mitochondrial Proteins metabolism, Axons metabolism, Neurons metabolism
- Abstract
Mitochondrial dynamics and trafficking are essential to provide the energy required for neurotransmission and neural activity. We investigated how G protein-coupled receptors (GPCRs) and G proteins control mitochondrial dynamics and trafficking. The activation of Gα
q inhibited mitochondrial trafficking in neurons through a mechanism that was independent of the canonical downstream PLCβ pathway. Mitoproteome analysis revealed that Gαq interacted with the Eutherian-specific mitochondrial protein armadillo repeat-containing X-linked protein 3 (Alex3) and the Miro1/Trak2 complex, which acts as an adaptor for motor proteins involved in mitochondrial trafficking along dendrites and axons. By generating a CNS-specific Alex3 knockout mouse line, we demonstrated that Alex3 was required for the effects of Gαq on mitochondrial trafficking and dendritic growth in neurons. Alex3-deficient mice had altered amounts of ER stress response proteins, increased neuronal death, motor neuron loss, and severe motor deficits. These data revealed a mammalian-specific Alex3/Gαq mitochondrial complex, which enables control of mitochondrial trafficking and neuronal death by GPCRs.- Published
- 2024
- Full Text
- View/download PDF
7. The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.
- Author
-
Acevedo A, Jones AE, Danna BT, Turner R, Montales KP, Benincá C, Reue K, Shirihai OS, Stiles L, Wallace M, Wang Y, Bertholet AM, and Divakaruni AS
- Abstract
Elevated levels of branched chain amino acids (BCAAs) and branched-chain α-ketoacids (BCKAs) are associated with cardiovascular and metabolic disease, but the molecular mechanisms underlying a putative causal relationship remain unclear. The branched-chain ketoacid dehydrogenase kinase (BCKDK) inhibitor BT2 is often used in preclinical models to increase BCAA oxidation and restore steady-state BCAA and BCKA levels. BT2 administration is protective in various rodent models of heart failure and metabolic disease, but confoundingly, targeted ablation of Bckdk in specific tissues does not reproduce the beneficial effects conferred by pharmacologic inhibition. Here we demonstrate that BT2, a lipophilic weak acid, can act as a mitochondrial uncoupler. Measurements of oxygen consumption, mitochondrial membrane potential, and patch-clamp electrophysiology show BT2 increases proton conductance across the mitochondrial inner membrane independently of its inhibitory effect on BCKDK. BT2 is roughly five-fold less potent than the prototypical uncoupler 2,4-dinitrophenol (DNP), and phenocopies DNP in lowering de novo lipogenesis and mitochondrial superoxide production. The data suggest the therapeutic efficacy of BT2 may be attributable to the well-documented effects of mitochondrial uncoupling in alleviating cardiovascular and metabolic disease.
- Published
- 2023
- Full Text
- View/download PDF
8. Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies.
- Author
-
Acin-Perez R, Benincá C, Fernandez Del Rio L, Shu C, Baghdasarian S, Zanette V, Gerle C, Jiko C, Khairallah R, Khan S, Rincon Fernandez Pacheco D, Shabane B, Erion K, Masand R, Dugar S, Ghenoiu C, Schreiner G, Stiles L, Liesa M, and Shirihai OS
- Subjects
- Mice, Animals, Proton-Translocating ATPases metabolism, Proteins metabolism, Homeostasis, Hydrolysis, Adenosine Triphosphate metabolism, Mitochondria metabolism
- Abstract
The maintenance of cellular function relies on the close regulation of adenosine triphosphate (ATP) synthesis and hydrolysis. ATP hydrolysis by mitochondrial ATP Synthase (CV) is induced by loss of proton motive force and inhibited by the mitochondrial protein ATPase inhibitor (ATPIF1). The extent of CV hydrolytic activity and its impact on cellular energetics remains unknown due to the lack of selective hydrolysis inhibitors of CV. We find that CV hydrolytic activity takes place in coupled intact mitochondria and is increased by respiratory chain defects. We identified (+)-Epicatechin as a selective inhibitor of ATP hydrolysis that binds CV while preventing the binding of ATPIF1. In cells with Complex-III deficiency, we show that inhibition of CV hydrolytic activity by (+)-Epichatechin is sufficient to restore ATP content without restoring respiratory function. Inhibition of CV-ATP hydrolysis in a mouse model of Duchenne Muscular Dystrophy is sufficient to improve muscle force without any increase in mitochondrial content. We conclude that the impact of compromised mitochondrial respiration can be lessened using hydrolysis-selective inhibitors of CV., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2023
- Full Text
- View/download PDF
9. A novel approach to measure complex V ATP hydrolysis in frozen cell lysates and tissue homogenates.
- Author
-
Fernandez-Del-Rio L, Benincá C, Villalobos F, Shu C, Stiles L, Liesa M, Divakaruni AS, Acin-Perez R, and Shirihai OS
- Subjects
- Hydrolysis, Mitochondria metabolism, Adenosine Triphosphate, Mitochondrial Proton-Translocating ATPases metabolism
- Abstract
Mitochondrial depolarization can initiate reversal activity of ATP synthase, depleting ATP by its hydrolysis. We have recently shown that increased ATP hydrolysis contributes to ATP depletion leading to a maladaptation in mitochondrial disorders, where maximal hydrolytic capacity per CV content is increasing. However, despite its importance, ATP hydrolysis is not a commonly studied parameter because of the limitations of the currently available methods. Methods that measure CV hydrolytic activity indirectly require the isolation of mitochondria and involve the introduction of detergents, preventing their utilization in clinical studies or any high-throughput analyses. Here, we describe a novel approach to assess maximal ATP hydrolytic capacity and maximal respiratory capacity in a single assay in cell lysates, PBMCs, and tissue homogenates that were previously frozen. The methodology described here has the potential to be used in clinical samples to determine adaptive and maladaptive adjustments of CV function in diseases, with the added benefit of being able to use frozen samples in a high-throughput manner and to explore ATP hydrolysis as a drug target for disease treatment., (© 2023 Fernandez-del-Rio et al.)
- Published
- 2023
- Full Text
- View/download PDF
10. NDUFV1 mutations in complex I deficiency: Case reports and review of symptoms.
- Author
-
Zanette V, Valle DD, Telles BA, Robinson AJ, Monteiro V, Santos MLSF, Souza RLR, and Benincá C
- Abstract
Mitochondrial complex I (CI) deficiency is the most common oxidative phosphorylation disorder described. It shows a wide range of phenotypes with poor correlation within genotypes. Herein we expand the clinics and genetics of CI deficiency in the brazilian population by reporting three patients with pathogenic (c.640G>A, c.1268C>T, c.1207dupG) and likely pathogenic (c.766C>T) variants in the NDUFV1 gene. We show the mutation c.766C>T associated with a childhood onset phenotype of hypotonia, muscle weakness, psychomotor regression, lethargy, dysphagia, and strabismus. Additionally, this mutation was found to be associated with headaches and exercise intolerance in adulthood. We also review reported pathogenic variants in NDUFV1 highlighting the wide phenotypic heterogeneity in CI deficiency.
- Published
- 2021
- Full Text
- View/download PDF
11. Utilization of Human Samples for Assessment of Mitochondrial Bioenergetics: Gold Standards, Limitations, and Future Perspectives.
- Author
-
Acin-Perez R, Benincá C, Shabane B, Shirihai OS, and Stiles L
- Abstract
Mitochondrial bioenergetic function is a central component of cellular metabolism in health and disease. Mitochondrial oxidative phosphorylation is critical for maintaining energetic homeostasis, and impairment of mitochondrial function underlies the development and progression of metabolic diseases and aging. However, measurement of mitochondrial bioenergetic function can be challenging in human samples due to limitations in the size of the collected sample. Furthermore, the collection of samples from human cohorts is often spread over multiple days and locations, which makes immediate sample processing and bioenergetics analysis challenging. Therefore, sample selection and choice of tests should be carefully considered. Basic research, clinical trials, and mitochondrial disease diagnosis rely primarily on skeletal muscle samples. However, obtaining skeletal muscle biopsies requires an appropriate clinical setting and specialized personnel, making skeletal muscle a less suitable tissue for certain research studies. Circulating white blood cells and platelets offer a promising primary tissue alternative to biopsies for the study of mitochondrial bioenergetics. Recent advances in frozen respirometry protocols combined with the utilization of minimally invasive and non-invasive samples may provide promise for future mitochondrial research studies in humans. Here we review the human samples commonly used for the measurement of mitochondrial bioenergetics with a focus on the advantages and limitations of each sample.
- Published
- 2021
- Full Text
- View/download PDF
12. Neural stem cells traffic functional mitochondria via extracellular vesicles.
- Author
-
Peruzzotti-Jametti L, Bernstock JD, Willis CM, Manferrari G, Rogall R, Fernandez-Vizarra E, Williamson JC, Braga A, van den Bosch A, Leonardi T, Krzak G, Kittel Á, Benincá C, Vicario N, Tan S, Bastos C, Bicci I, Iraci N, Smith JA, Peacock B, Muller KH, Lehner PJ, Buzas EI, Faria N, Zeviani M, Frezza C, Brisson A, Matheson NJ, Viscomi C, and Pluchino S
- Subjects
- Animals, Biological Transport, Cells, Cultured, Female, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Mesenchymal Stem Cells metabolism, Mesenchymal Stem Cells physiology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neural Stem Cells ultrastructure, Extracellular Vesicles metabolism, Mitochondria metabolism, Neural Stem Cells metabolism
- 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., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: SP is co-founder, CSO and shareholder (>5%) of CITC Ltd. and iSTEM Therapeutics Litd., and co-founder and Non-executive Director at asitia Therapeutics Ltd.; LPJ is shareholder of CITC Ltd.; JAS is a Project Manager and Senior Research Associate at CITC Ltd. and Director of Research of iSTEM Therapeutics Ltd.; BP is an employee of NanoFCM and his contributions to this paper were made as part of their employment.
- Published
- 2021
- Full Text
- View/download PDF
13. Tetra-arylborate lipophilic anions as targeting groups.
- Author
-
Gaddale Devanna KK, Gawel JM, Prime TA, Cvetko F, Benincá C, Caldwell ST, Negoda A, Harrison A, James AM, Pavlov EV, Murphy MP, and Hartley RC
- Subjects
- Biological Transport, Cell Line, Tumor, Humans, Hydrogen-Ion Concentration, Lysosomes metabolism, Models, Molecular, Molecular Conformation, Borates chemistry, Borates metabolism, Hydrophobic and Hydrophilic Interactions
- Abstract
Tetraphenylborate (TPB) anions traverse membranes but are excluded from mitochondria by the membrane potential (Δψ). TPB-conjugates also distributed across membranes in response to Δψ, but surprisingly, they rapidly entered cells. They accumulated within lysosomes following endocystosis. This pH-independent targeting of lysosomes makes possible new classes of probe and bioactive molecules.
- Published
- 2021
- Full Text
- View/download PDF
14. Mutation in the MICOS subunit gene APOO (MIC26) associated with an X-linked recessive mitochondrial myopathy, lactic acidosis, cognitive impairment and autistic features.
- Author
-
Benincá C, Zanette V, Brischigliaro M, Johnson M, Reyes A, Valle DAD, J Robinson A, Degiorgi A, Yeates A, Telles BA, Prudent J, Baruffini E, S F Santos ML, R de Souza RL, Fernandez-Vizarra E, Whitworth AJ, and Zeviani M
- Subjects
- Acidosis, Lactic genetics, Acidosis, Lactic pathology, Animals, Autistic Disorder pathology, Cognitive Dysfunction pathology, Drosophila melanogaster genetics, Fibroblasts metabolism, Genetic Diseases, X-Linked genetics, Genetic Diseases, X-Linked pathology, Humans, Mitochondrial Membranes metabolism, Mitochondrial Membranes pathology, Mitochondrial Myopathies epidemiology, Mitochondrial Myopathies pathology, Protein Binding, Saccharomyces cerevisiae genetics, Apolipoproteins genetics, Autistic Disorder genetics, Cognitive Dysfunction genetics, Membrane Proteins genetics, Mitochondrial Myopathies genetics, Mitochondrial Proteins genetics, Saccharomyces cerevisiae Proteins genetics
- Abstract
Background: Mitochondria provide ATP through the process of oxidative phosphorylation, physically located in the inner mitochondrial membrane (IMM). The mitochondrial contact site and organising system (MICOS) complex is known as the 'mitoskeleton' due to its role in maintaining IMM architecture. APOO encodes MIC26, a component of MICOS, whose exact function in its maintenance or assembly has still not been completely elucidated., Methods: We have studied a family in which the most affected subject presented progressive developmental delay, lactic acidosis, muscle weakness, hypotonia, weight loss, gastrointestinal and body temperature dysautonomia, repetitive infections, cognitive impairment and autistic behaviour. Other family members showed variable phenotype presentation. Whole exome sequencing was used to screen for pathological variants. Patient-derived skin fibroblasts were used to confirm the pathogenicity of the variant found in APOO . Knockout models in Drosophila melanogaster and Saccharomyces cerevisiae were employed to validate MIC26 involvement in MICOS assembly and mitochondrial function., Results: A likely pathogenic c.350T>C transition was found in APOO predicting an I117T substitution in MIC26. The mutation caused impaired processing of the protein during import and faulty insertion into the IMM. This was associated with altered MICOS assembly and cristae junction disruption. The corresponding mutation in MIC26 or complete loss was associated with mitochondrial structural and functional deficiencies in yeast and D. melanogaster models., Conclusion: This is the first case of pathogenic mutation in APOO , causing altered MICOS assembly and neuromuscular impairment. MIC26 is involved in the assembly or stability of MICOS in humans, yeast and flies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2021
- Full Text
- View/download PDF
15. Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations.
- Author
-
Zanette V, Reyes A, Johnson M, do Valle D, Robinson AJ, Monteiro V, Telles BA, L R Souza R, S F Santos ML, Benincá C, and Zeviani M
- Abstract
Objective: To expand the clinical phenotype of POLR3A mutations by assessing the functional consequences of a missense and a splicing acceptor mutation., Methods: We performed whole-exome sequencing for identification of likely pathogenic mutations in a 9-year-old female patient with severe generalized dystonia, metabolic acidosis, leukocytosis, hypotonia, and dysphagia. Brain MRI showed basal ganglia atrophy and presence of lactate and lipid peaks by [
1 H]-magnetic resonance spectroscopy. Expression levels of Pol III target genes were measured by quantitative real-time (qRT)-PCR to study the pathogenicity of the biallelic mutations in patient fibroblasts., Results: The patient is a compound heterozygous for a novel missense c.3721G>A (p.Val1241Met) and the splicing region c.1771-6C>G mutation in POLR3A , the gene coding for the catalytic subunit of RNA polymerase III (Pol III). Aberrant splicing was observed for the c.1771-6C>G mutation. Decreased RNA expression levels of Pol III targets (HNRNPH2, ubiquitin B, lactotransferrin, and HSP90AA1) were observed in patient fibroblasts with rescue to normal levels by overexpression of the wild-type protein but not by the p.Val1241Met variant., Conclusions: Mutations in the POLR3A gene cause POLR3A -related hypomyelinating leukodystrophy with or without oligodontia or hypogonadotropic hypogonadism (HLD7, OMIM: 607694) and neonatal progeroid syndrome (OMIM: 264090), both with high phenotypic variability. We demonstrated the pathogenicity of c.1771-6C>G and c.3721G>A mutations causing an early-onset disorder. The phenotype of our patient expands the clinical presentation of POLR3A -related mutations and suggests a new classification that we propose designating as Neurodevelopmental Disorder with Regression, Abnormal Movements, and Increased Lactate., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)- Published
- 2020
- Full Text
- View/download PDF
16. Opa1 Overexpression Protects from Early-Onset Mpv17 -/- -Related Mouse Kidney Disease.
- Author
-
Luna-Sanchez M, Benincá C, Cerutti R, Brea-Calvo G, Yeates A, Scorrano L, Zeviani M, and Viscomi C
- Subjects
- Animals, Apoptosis genetics, DNA, Mitochondrial, Disease Models, Animal, Disease Susceptibility, GTP Phosphohydrolases metabolism, Immunohistochemistry, Kidney Diseases pathology, Mice, Mice, Knockout, Mitochondria genetics, Mitochondria metabolism, Mitochondrial Proteins genetics, Mitochondrial Proteins metabolism, Models, Biological, Oxidative Phosphorylation, Podocytes metabolism, Podocytes pathology, Podocytes ultrastructure, GTP Phosphohydrolases genetics, Gene Expression, Kidney Diseases etiology, Kidney Diseases metabolism, Membrane Proteins deficiency
- Abstract
Moderate overexpression of Opa1, the master regulator of mitochondrial cristae morphology, significantly improved mitochondrial damage induced by drugs, surgical denervation, or oxidative phosphorylation (OXPHOS) defects due to specific impairment of a single mitochondrial respiratory chain complex. Here, we investigated the effectiveness of this approach in the Mpv17
-/- mouse, characterized by profound, multisystem mitochondrial DNA (mtDNA) depletion. After the crossing with Opa1tg mice, we found a surprising anticipation of the severe, progressive focal segmental glomerulosclerosis, previously described in Mpv17-/- animals as a late-onset clinical feature (after 12-18 months of life). In contrast, Mpv17-/- animals from this new "mixed" strain died at 8-9 weeks after birth because of severe kidney failure However, Mpv17-/- ::Opa1tg mice lived much longer than Mpv17-/- littermates and developed the kidney dysfunction much later. mtDNA content and OXPHOS activities were significantly higher in Mpv17-/- ::Opa1tg than in Mpv17-/- kidneys and similar to those for wild-type (WT) littermates. Mitochondrial network and cristae ultrastructure were largely preserved in Mpv17-/- ::Opa1tg versus Mpv17-/- kidney and isolated podocytes. Mechanistically, the protective effect of Opa1 overexpression in this model was mediated by a block in apoptosis due to the stabilization of the mitochondrial cristae. These results demonstrate that strategies aiming at increasing Opa1 expression or activity can be effective against mtDNA depletion syndromes., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2020
- Full Text
- View/download PDF
17. Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7.
- Author
-
Mohanraj K, Wasilewski M, Benincá C, Cysewski D, Poznanski J, Sakowska P, Bugajska Z, Deckers M, Dennerlein S, Fernandez-Vizarra E, Rehling P, Dadlez M, Zeviani M, and Chacinska A
- Subjects
- Cytosol drug effects, Cytosol metabolism, Disulfides metabolism, Electron Transport drug effects, Fibroblasts drug effects, Fibroblasts metabolism, HEK293 Cells, HeLa Cells, Humans, Mitochondria drug effects, Mitochondria metabolism, Mitochondrial Membrane Transport Proteins metabolism, Mitochondrial Membranes drug effects, Mitochondrial Membranes metabolism, Mitochondrial Precursor Protein Import Complex Proteins, Mutant Proteins metabolism, Oxidation-Reduction drug effects, Protein Binding drug effects, Protein Transport drug effects, Ubiquitin metabolism, Mitochondrial Proteins metabolism, Mutation genetics, Proteasome Endopeptidase Complex metabolism, Proteasome Inhibitors pharmacology
- 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., (© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2019
- Full Text
- View/download PDF
18. APOPT1/COA8 assists COX assembly and is oppositely regulated by UPS and ROS.
- Author
-
Signes A, Cerutti R, Dickson AS, Benincá C, Hinchy EC, Ghezzi D, Carrozzo R, Bertini E, Murphy MP, Nathan JA, Viscomi C, Fernandez-Vizarra E, and Zeviani M
- Subjects
- Animals, Apoptosis Regulatory Proteins deficiency, Cells, Cultured, Genetic Complementation Test, Humans, Mice, Mice, Knockout, Mitochondrial Proteins deficiency, Apoptosis Regulatory Proteins metabolism, Electron Transport Complex IV metabolism, Mitochondrial Proteins metabolism, Protein Multimerization, Reactive Oxygen Species metabolism, Unfolded Protein Response
- 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., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2019
- Full Text
- View/download PDF
19. Perturbed Redox Signaling Exacerbates a Mitochondrial Myopathy.
- Author
-
Dogan SA, Cerutti R, Benincá C, Brea-Calvo G, Jacobs HT, Zeviani M, Szibor M, and Viscomi C
- Subjects
- Animals, Autophagy, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondrial Myopathies genetics, Mitochondrial Myopathies pathology, Mitochondrial Proteins genetics, Muscle, Skeletal metabolism, Muscle, Skeletal pathology, Organelle Biogenesis, Oxidation-Reduction, Oxidoreductases genetics, Plant Proteins genetics, Mitochondrial Myopathies metabolism, Mitochondrial Proteins metabolism, Oxidoreductases metabolism, Plant Proteins metabolism, Reactive Oxygen Species metabolism, Signal Transduction
- Abstract
Alternative oxidases (AOXs) bypass respiratory complexes III and IV by transferring electrons from coenzyme Q directly to O
2 . They have therefore been proposed as a potential therapeutic tool for mitochondrial diseases. We crossed the severely myopathic skeletal muscle-specific COX15 knockout (KO) mouse with an AOX-transgenic mouse. Surprisingly, the double KO-AOX mutants had decreased lifespan and a substantial worsening of the myopathy compared with KO alone. Decreased ROS production in KO-AOX versus KO mice led to impaired AMPK/PGC-1α signaling and PAX7/MYOD-dependent muscle regeneration, blunting compensatory responses. Importantly, the antioxidant N-acetylcysteine had a similar effect, decreasing the lifespan of KO mice. Our findings have major implications for understanding pathogenic mechanisms in mitochondrial diseases and for the design of therapies, highlighting the benefits of ROS signaling and the potential hazards of antioxidant treatment., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
20. Rapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis.
- Author
-
Civiletto G, Dogan SA, Cerutti R, Fagiolari G, Moggio M, Lamperti C, Benincá C, Viscomi C, and Zeviani M
- Subjects
- Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Electron Transport Complex IV metabolism, Lysosomes drug effects, Mice, Inbred C57BL, Mice, Knockout, Mitochondria drug effects, Mitochondria metabolism, Mitochondria ultrastructure, Mitochondrial Myopathies metabolism, Motor Activity drug effects, Muscles drug effects, Muscles pathology, Phenotype, Rilmenidine pharmacology, TOR Serine-Threonine Kinases metabolism, Autophagy drug effects, Lysosomes metabolism, Mitochondrial Myopathies pathology, Organelle Biogenesis, Sirolimus pharmacology
- Abstract
The mTOR inhibitor rapamycin ameliorates the clinical and biochemical phenotype of mouse, worm, and cellular models of mitochondrial disease, via an unclear mechanism. Here, we show that prolonged rapamycin treatment improved motor endurance, corrected morphological abnormalities of muscle, and increased cytochrome c oxidase (COX) activity of a muscle-specific Cox15 knockout mouse ( Cox15
sm / sm ). Rapamycin treatment restored autophagic flux, which was impaired in naïve Cox15sm / sm muscle, and reduced the number of damaged mitochondria, which accumulated in untreated Cox15sm / sm mice. Conversely, rilmenidine, an mTORC1-independent autophagy inducer, was ineffective on the myopathic features of Cox15sm / sm animals. This stark difference supports the idea that inhibition of mTORC1 by rapamycin has a key role in the improvement of the mitochondrial function in Cox15sm / sm muscle. In contrast to rilmenidine, rapamycin treatment also activated lysosomal biogenesis in muscle. This effect was associated with increased nuclear localization of TFEB, a master regulator of lysosomal biogenesis, which is inhibited by mTORC1-dependent phosphorylation. We propose that the coordinated activation of autophagic flux and lysosomal biogenesis contribute to the effective clearance of dysfunctional mitochondria by rapamycin., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)- Published
- 2018
- Full Text
- View/download PDF
21. Basal mitophagy is widespread in Drosophila but minimally affected by loss of Pink1 or parkin.
- Author
-
Lee JJ, Sanchez-Martinez A, Martinez Zarate A, Benincá C, Mayor U, Clague MJ, and Whitworth AJ
- Subjects
- Animals, Genes, Reporter, Larva metabolism, Lysosomes metabolism, Mutation genetics, Organ Specificity, Reproducibility of Results, Drosophila Proteins metabolism, Drosophila melanogaster metabolism, Mitophagy, Protein Serine-Threonine Kinases metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
The Parkinson's disease factors PINK1 and parkin are strongly implicated in stress-induced mitophagy in vitro, but little is known about their impact on basal mitophagy in vivo. We generated transgenic Drosophila melanogaster expressing fluorescent mitophagy reporters to evaluate the impact of Pink1/parkin mutations on basal mitophagy under physiological conditions. We find that mitophagy is readily detectable and abundant in many tissues, including Parkinson's disease-relevant dopaminergic neurons. However, we did not detect mitolysosomes in flight muscle. Surprisingly, in Pink1 or parkin null flies, we did not observe any substantial impact on basal mitophagy. Because these flies exhibit locomotor defects and dopaminergic neuron loss, our findings raise questions about current assumptions of the pathogenic mechanism associated with the PINK1/parkin pathway. Our findings provide evidence that Pink1 and parkin are not essential for bulk basal mitophagy in Drosophila They also emphasize that mechanisms underpinning basal mitophagy remain largely obscure., (© 2018 University of Cambridge.)
- Published
- 2018
- Full Text
- View/download PDF
22. Ablation of the stress protease OMA1 protects against heart failure in mice.
- Author
-
Acin-Perez R, Lechuga-Vieco AV, Del Mar Muñoz M, Nieto-Arellano R, Torroja C, Sánchez-Cabo F, Jiménez C, González-Guerra A, Carrascoso I, Benincá C, Quiros PM, López-Otín C, Castellano JM, Ruíz-Cabello J, Jiménez-Borreguero LJ, and Enríquez JA
- Subjects
- Animals, Heart Failure genetics, Male, Metalloproteases genetics, Mice, Mitochondria metabolism, Mitochondrial Proteins genetics, Myocytes, Cardiac metabolism, Reactive Oxygen Species metabolism, Heart Failure metabolism, Metalloproteases metabolism, Mitochondrial Proteins metabolism
- Abstract
Heart failure (HF) is a major health and economic burden in developed countries. It has been proposed that the pathogenesis of HF may involve the action of mitochondria. We evaluate three different mouse models of HF: tachycardiomyopathy, HF with preserved left ventricular (LV) ejection fraction (LVEF), and LV myocardial ischemia and hypertrophy. Regardless of whether LVEF is preserved, our results indicate that the three models share common features: an increase in mitochondrial reactive oxygen species followed by ultrastructural alterations in the mitochondrial cristae and loss of mitochondrial integrity that lead to cardiomyocyte death. We show that the ablation of the mitochondrial protease OMA1 averts cardiomyocyte death in all three murine HF models, and thus loss of OMA1 plays a direct role in cardiomyocyte protection. This finding identifies OMA1 as a potential target for preventing the progression of myocardial damage in HF associated with a variety of etiologies., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2018
- Full Text
- View/download PDF
23. Removal of clomazone herbicide from a synthetic effluent by electrocoagulation.
- Author
-
Benincá C, Vargas FT, Martins ML, Gonçalves FF, Vargas RP, Freire FB, and Zanoelo EF
- Subjects
- Aluminum analysis, Electricity, Electrodes, Waste Disposal, Fluid instrumentation, Herbicides chemistry, Isoxazoles chemistry, Oxazolidinones chemistry, Waste Disposal, Fluid methods, Water Pollutants, Chemical chemistry
- Abstract
The aim of this work was to investigate the kinetics of removal of clomazone herbicide from an aqueous solution by electrocoagulation. The experiments were performed in a cylindrical batch reactor with six aluminum electrodes in monopolar mode, arranged in series and connected to a digital DC power. The aqueous solution (tap water + clomazone) with initial pH close to 7.9 was always treated at ambient temperature (≈20 °C) and atmospheric pressure for 5,400 s. For a confidence level of 95% the rate constant of electrocoagulation and the efficiency of removal of clomazone at equilibrium were 2.1 × 10(-3) ± 0.5 × 10(-3) s(-1) and 97.7 ± 2.2%, respectively. The final chemical oxygen demand was 88% lower than that measured initially, while turbidity and apparent color were totally removed from the synthetic solution at a rate close to that of formation of aluminum hydroxides. Some reaction intermediates, such as benzonitrile-2-chloro and 2-chloro-hex-2,4-diene-1,6-dioic-acid determined by gas chromatography mass spectrometry (GC-MS) analysis, explain the ratio of equilibrium to initial total organic carbon approximately between 0.6 and 0.8 at a probability of 95%.
- Published
- 2016
- Full Text
- View/download PDF
24. Gαq signalling: the new and the old.
- Author
-
Sánchez-Fernández G, Cabezudo S, García-Hoz C, Benincá C, Aragay AM, Mayor F Jr, and Ribas C
- Subjects
- Cellular Microenvironment, GTP-Binding Protein alpha Subunits, Gq-G11 chemistry, Humans, MAP Kinase Kinase 5 metabolism, Phosphatidylinositol 3-Kinases metabolism, Phospholipase C beta metabolism, Proto-Oncogene Proteins c-akt metabolism, Receptors, G-Protein-Coupled metabolism, Signal Transduction, rhoA GTP-Binding Protein metabolism, GTP-Binding Protein alpha Subunits, Gq-G11 metabolism
- Abstract
In the last few years the interactome of Gαq has expanded considerably, contributing to improve our understanding of the cellular and physiological events controlled by this G alpha subunit. The availability of high-resolution crystal structures has led the identification of an effector-binding region within the surface of Gαq that is able to recognise a variety of effector proteins. Consequently, it has been possible to ascribe different Gαq functions to specific cellular players and to identify important processes that are triggered independently of the canonical activation of phospholipase Cβ (PLCβ), the first identified Gαq effector. Novel effectors include p63RhoGEF, that provides a link between G protein-coupled receptors and RhoA activation, phosphatidylinositol 3-kinase (PI3K), implicated in the regulation of the Akt pathway, or the cold-activated TRPM8 channel, which is directly inhibited upon Gαq binding. Recently, the activation of ERK5 MAPK by Gq-coupled receptors has also been described as a novel PLCβ-independent signalling axis that relies upon the interaction between this G protein and two novel effectors (PKCζ and MEK5). Additionally, the association of Gαq with different regulatory proteins can modulate its effector coupling ability and, therefore, its signalling potential. Regulators include accessory proteins that facilitate effector activation or, alternatively, inhibitory proteins that downregulate effector binding or promote signal termination. Moreover, Gαq is known to interact with several components of the cytoskeleton as well as with important organisers of membrane microdomains, which suggests that efficient signalling complexes might be confined to specific subcellular environments. Overall, the complex interaction network of Gαq underlies an ever-expanding functional diversity that puts forward this G alpha subunit as a major player in the control of physiological functions and in the development of different pathological situations., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
25. A new non-canonical pathway of Gα(q) protein regulating mitochondrial dynamics and bioenergetics.
- Author
-
Benincá C, Planagumà J, de Freitas Shuck A, Acín-Perez R, Muñoz JP, de Almeida MM, Brown JH, Murphy AN, Zorzano A, Enríquez JA, and Aragay AM
- Subjects
- Animals, Cell Line, Dynamins metabolism, GTP Phosphohydrolases metabolism, GTP-Binding Protein alpha Subunits, Gq-G11 antagonists & inhibitors, GTP-Binding Protein alpha Subunits, Gq-G11 genetics, HEK293 Cells, Humans, Membrane Potential, Mitochondrial, Mice, Mice, Transgenic, Mitochondria metabolism, Mitochondrial Dynamics, Mitochondrial Membranes metabolism, NIH 3T3 Cells, Oxidative Phosphorylation, Protein Subunits antagonists & inhibitors, Protein Subunits genetics, Protein Subunits metabolism, RNA, Small Interfering metabolism, Energy Metabolism, GTP-Binding Protein alpha Subunits, Gq-G11 metabolism
- Abstract
Contrary to previous assumptions, G proteins do not permanently reside on the plasma membrane, but are constantly monitoring the cytoplasmic surfaces of the plasma membrane and endomembranes. Here, we report that the Gαq and Gα11 proteins locate at the mitochondria and play a role in a complex signaling pathway that regulates mitochondrial dynamics. Our results provide evidence for the presence of the heteromeric G protein (Gαq/11βγ) at the outer mitochondrial membrane and for Gαq at the inner membrane. Both localizations are necessary to maintain the proper equilibrium between fusion and fission; which is achieved by altering the activity of mitofusin proteins, Drp1, OPA1 and the membrane potential at both the outer and inner mitochondrial membranes. As a result of the absence of Gαq/11, there is a decrease in mitochondrial fusion rates and a decrease in overall respiratory capacity, ATP production and OXPHOS-dependent growth. These findings demonstrate that the presence of Gαq proteins at the mitochondria serves as a physiological function: stabilizing elongated mitochondria and regulating energy production in Drp1 and Opa1 dependent mechanisms. This thereby links organelle dynamics and physiology., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
26. Chronic genetic damages in Geophagus brasiliensis exposed to anthropic impact in estuarine lakes at Santa Catarina coast--southern of Brazil.
- Author
-
Benincá C, Ramsdorf W, Vicari T, de Oliveira Ribeiro CA, de Almeida MI, Silva de Assis HC, and Cestari MM
- Subjects
- Animals, Biomarkers, Brazil, Cholinesterase Inhibitors metabolism, Comet Assay, DNA Damage genetics, Ecosystem, Kidney drug effects, Kidney pathology, Liver drug effects, Liver pathology, Water Pollutants, Chemical analysis, DNA Damage drug effects, Fishes genetics, Lakes chemistry
- Abstract
Biological monitoring through animals exposed to pollutants using biomarkers provides a promising tool for the identification of pollutants that may cause damage to human health and/or to sustainability of ecosystems. The effects of pollutants in fish tissues are important tools to understand the impact of human activities in natural ecosystems. The aim of this work was to study the water quality of two estuarine lakes in Santa Catarina, Brazil (Camacho Lake and Santa Marta Lake). Geophagus brasiliensis is a species widely distributed in Brazil and was used in this work. Comet assays in peripheral red blood and kidney cells, micronucleus tests in peripheral red blood cells, measurements of acetylcholinesterase activity in axial muscle and histopathological analysis of liver were used as biomarkers. Three sampling campaigns were undertaken in November 2004, June 2005 and November 2005. Thirty adult animals were sampled from each of three different sites (P1--Santa Marta Lake, P2 and P3--Camacho Lake). A negative control was sampled in a non-polluted site at Costa Ecological Park, Paraná. The positive control for genotoxicity was obtained by treating animals with copper sulphate. The results showed that both studied lakes are impacted by potential genotoxic substances. Severe lesions in liver of G. brasiliensis were also observed. The inhibition of acetylcholinesterase activity suggests the presence of pesticides or metals in the studied sites. This work shows that the water quality of Santa Marta and Camacho Lakes have been compromised and further control source of pollutants into these ecosystems is required.
- Published
- 2012
- Full Text
- View/download PDF
27. Chemical kinetics of 5-o-caffeoylquinic acid in superheated steam: effect of isomerization on mate (Ilex paraguariensis) manufacturing.
- Author
-
Zanoelo EF and Benincá C
- Subjects
- Caffeic Acids analysis, Chlorogenic Acid analogs & derivatives, Hot Temperature, Ilex paraguariensis chemistry, Isomerism, Kinetics, Models, Theoretical, Plant Leaves chemistry, Quinic Acid analysis, Quinic Acid chemistry, Steam, Caffeic Acids chemistry, Food Handling methods, Quinic Acid analogs & derivatives
- Abstract
A set of experiments was carried out to investigate the chemical stability of 5-o-caffeoylquinic acid (5-CQA) in the presence of superheated steam. A batch cylindrical reactor made of glass and isothermally operated between 398 and 499 K was used in the experiments. A high-performance liquid chromatograph equipped with a diode array detector was applied to monitor the 5-CQA concentrations. The conversions of 5-CQA were correctly reproduced with a simplified kinetic model represented by a reversible pseudofirst-order reaction of isomerization. The effect of temperature on the forward rate constant was represented by the Arrhenius equation with parameters tuned on experimental data. The heat of isomerization of 5-CQA and the equilibrium constant at 298 K were calculated by involving the integrated form of the van't Hoff equation. The observed reaction was revealed to not be detrimental for the quality of manufactured leaves and branches of mate because the content of total chlorogenic acids was not changed.
- Published
- 2009
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.