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1. Targeted Metabolomics Analysis Suggests That Tacrolimus Alters Protection against Oxidative Stress

Author

Marie Joncquel, Julie Labasque, Julie Demaret, Marie-Adélaïde Bout, Aghilès Hamroun, Benjamin Hennart, Mathieu Tronchon, Magali Defevre, Isabelle Kim, Alain Kerckhove, Laurence George, Mylène Gilleron, Anne-Frédérique Dessein, Farid Zerimech, and Guillaume Grzych

Subjects
pipecolic acid, immunosuppressive, tacrolimus, metabolomics, oxidative stress, Therapeutics. Pharmacology, RM1-950
Abstract

Tacrolimus (FK506) is an immunosuppressant that is experiencing a continuous rise in usage worldwide. The related side effects are known to be globally dose-dependent. Despite numerous studies on FK506, the mechanisms underlying FK506 toxicity are still not well understood. It is therefore essential to explore the toxicity mediated by FK506. To accomplish this, we conducted a targeted metabolomic analysis using LC−MS on the plasma samples of patients undergoing FK506 treatment. The aim was to identify any associated altered metabolic pathway. Another anti-calcineurin immunosuppressive therapy, ciclosporin (CSA), was also studied. Increased plasma concentrations of pipecolic acid (PA) and sarcosine, along with a decrease in the glycine/sarcosine ratio and a tendency of increased plasma lysine was observed in patients under FK506 compared to control samples. Patients under CSA do not show an increase in plasma PA compared to the control samples, which does not support a metabolic link between the calcineurin and PA. The metabolomics changes observed in patients under FK506 highlight a possible link between FK506 and the action of an enzyme involved in both PA and sarcosine catabolism and oxidative pathway, the Peroxisomal sarcosine oxidase (PIPOX). Moreover, PA could be investigated as a potential biomarker of early nephrotoxicity in the follow-up of patients under FK506.

Published
2023
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2. QIL1 mutation causes MICOS disassembly and early onset fatal mitochondrial encephalopathy with liver disease

Author

Virginia Guarani, Claude Jardel, Dominique Chrétien, Anne Lombès, Paule Bénit, Clémence Labasse, Emmanuelle Lacène, Agnès Bourillon, Apolline Imbard, Jean-François Benoist, Imen Dorboz, Mylène Gilleron, Eric S Goetzman, Pauline Gaignard, Abdelhamid Slama, Monique Elmaleh-Bergès, Norma B Romero, Pierre Rustin, Hélène Ogier de Baulny, Joao A Paulo, J Wade Harper, and Manuel Schiff

Subjects
QIL1, MICOS, mitochondrial disease, early-onset fatal mitochondrial encephalopathy, 3-methylglutaconic aciduria, liver disease, Medicine, Science, Biology (General), QH301-705.5
Abstract

Previously, we identified QIL1 as a subunit of mitochondrial contact site (MICOS) complex and demonstrated a role for QIL1 in MICOS assembly, mitochondrial respiration, and cristae formation critical for mitochondrial architecture (Guarani et al., 2015). Here, we identify QIL1 null alleles in two siblings displaying multiple clinical symptoms of early-onset fatal mitochondrial encephalopathy with liver disease, including defects in respiratory chain function in patient muscle. QIL1 absence in patients’ fibroblasts was associated with MICOS disassembly, abnormal cristae, mild cytochrome c oxidase defect, and sensitivity to glucose withdrawal. QIL1 expression rescued cristae defects, and promoted re-accumulation of MICOS subunits to facilitate MICOS assembly. MICOS assembly and cristae morphology were not efficiently rescued by over-expression of other MICOS subunits in patient fibroblasts. Taken together, these data provide the first evidence of altered MICOS assembly linked with a human mitochondrial disease and confirm a central role for QIL1 in stable MICOS complex formation.

Published
2016
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3. Mutations in CYC1, Encoding Cytochrome c1 Subunit of Respiratory Chain Complex III, Cause Insulin-Responsive Hyperglycemia

Author

Abdelhamid Slama, Anne Lombès, Sandra T. Cooper, Heni Abida, Chen-Hsien Su, Manuel Schiff, Alexander Tzagoloff, Kym Mina, Minal Menezes, Padma Sivadorai, Richard J.N. Allcock, Hélène Ogier de Baulny, Mylène Gilleron, John Christodoulou, Malgorzata Rak, David R. Thorburn, Nina Kresoje, Lisa G. Riley, Nigel G. Laing, Pierre Rustin, Mark R. Davis, Aurélien Bayot, and Pauline Gaignard

Subjects
Iron-Sulfur Proteins, Male, Models, Molecular, Saccharomyces cerevisiae Proteins, Cytochrome, Protein subunit, Molecular Sequence Data, Cytochromes c1, Saccharomyces cerevisiae, Mitochondrion, medicine.disease_cause, Electron Transport, 03 medical and health sciences, Consanguinity, 0302 clinical medicine, Cytochrome C1, Report, medicine, Genetics, Humans, Insulin, Genetics(clinical), Amino Acid Sequence, Genetics (clinical), 030304 developmental biology, Skin, 0303 health sciences, Mutation, biology, Cytochrome b, Genetic Complementation Test, Cytochromes c, Ketosis, Fibroblasts, Molecular biology, Mitochondrial respiratory chain complex III, 3. Good health, Mitochondria, Protein Subunits, Coenzyme Q – cytochrome c reductase, Child, Preschool, Hyperglycemia, biology.protein, Female, 030217 neurology & neurosurgery
Abstract

Many individuals with abnormalities of mitochondrial respiratory chain complex III remain genetically undefined. Here, we report mutations (c.288G>T [p.Trp96Cys] and c.643C>T [p.Leu215Phe]) in CYC1, encoding the cytochrome c1 subunit of complex III, in two unrelated children presenting with recurrent episodes of ketoacidosis and insulin-responsive hyperglycemia. Cytochrome c1, the heme-containing component of complex III, mediates the transfer of electrons from the Rieske iron-sulfur protein to cytochrome c. Cytochrome c1 is present at reduced levels in the skeletal muscle and skin fibroblasts of affected individuals. Moreover, studies on yeast mutants and affected individuals’ fibroblasts have shown that exogenous expression of wild-type CYC1 rescues complex III activity, demonstrating the deleterious effect of each mutation on cytochrome c1 stability and complex III activity.

Published
2013
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4. Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders

Author

Laurence Jonard, Xiaowu Gai, Hongbo Xie, Valérie Desquiret-Dumas, Claude Jardel, Gaëlle Hardy, Patrizia Amati-Bonneau, Catherine Florentz, Marni J. Falk, Nadia Aoutil, Agnès Rötig, Marc Ferré, Isabelle Durand-Zaleski, Annabelle Chaussenot, Hassani Maoulida, Delphine Martinez, Sylvie Bannwarth, Claire Hoarau, Anne-Sophie Lebre, Brigitte Chabrol, Konstantina Fragaki, Abdelhamid Slama, Bénédicte Mousson de Camaret, Vincent Procaccio, Pauline Gaignard, Jennifer Ceresuela, Jean-Paul Bonnefont, Véronique Paquis-Flucklinger, Kim-Hanh Le Quan Sang, Mylène Gilleron, Pascal Reynier, Claire Marie Dhaenens, Christophe Rocher, Nathanaël Charrier, Aurore Devos, Sandrine Marlin, Caroline Espil-Taris, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Hôpital Archet 2 [Nice] (CHU), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), URCEco, Hôpital Hôtel-Dieu [Paris], Children’s Hospital of Philadelphia (CHOP ), Centre Hospitalier Universitaire [Grenoble] (CHU), Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL), CHU Lyon, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Physiopathologie mitochondriale, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), and Université Nice Sophia Antipolis (1965 - 2019) (UNS)

Subjects
Adult, Male, Mitochondrial DNA, Mitochondrial Diseases, Mutation Report, Adolescent, [SDV]Life Sciences [q-bio], Mitochondrial disease, Biology, medicine.disease_cause, DNA, Mitochondrial, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Rare mutations, Prevalence, Genetics, medicine, Humans, Patient cohort, Age of Onset, Child, Gene, Genetics (clinical), Aged, 030304 developmental biology, 0303 health sciences, Mutation, Homoplasmy, Infant, Newborn, Infant, Middle Aged, medicine.disease, Phenotype, Heteroplasmy, 3. Good health, Child, Preschool, Female, Age of onset, 030217 neurology & neurosurgery
Abstract

International audience; BACKGROUND: Mitochondrial DNA (mtDNA) diseases are rare disorders whose prevalence is estimated around 1 in 5000. Patients are usually tested only for deletions and for common mutations of mtDNA which account for 5-40% of cases, depending on the study. However, the prevalence of rare mtDNA mutations is not known. METHODS: We analysed the whole mtDNA in a cohort of 743 patients suspected of manifesting a mitochondrial disease, after excluding deletions and common mutations. Both heteroplasmic and homoplasmic variants were identified using two complementary strategies (Surveyor and MitoChip). Multiple correspondence analyses followed by hierarchical ascendant cluster process were used to explore relationships between clinical spectrum, age at onset and localisation of mutations. RESULTS: 7.4% of deleterious mutations and 22.4% of novel putative mutations were identified. Pathogenic heteroplasmic mutations were more frequent than homoplasmic mutations (4.6% vs 2.8%). Patients carrying deleterious mutations showed symptoms before 16 years of age in 67% of cases. Early onset disease (16 years) were associated with mutations in tRNA genes. MTND5 and MTND6 genes were identified as 'hotspots' of mutations, with Leigh syndrome accounting for the large majority of associated phenotypes. CONCLUSIONS: Rare mitochondrial DNA mutations probably account for more than 7.4% of patients with respiratory chain deficiency. This study shows that a comprehensive analysis of mtDNA is essential, and should include young children, for an accurate diagnosis that is now accessible with the development of next generation sequencing technology.

Published
2013

5. QIL1 mutation causes MICOS disassembly and early onset fatal mitochondrial encephalopathy with liver disease

Author

Emmanuelle Lacène, Mylène Gilleron, Manuel Schiff, Joao A. Paulo, Eric S. Goetzman, Virginia Guarani, Monique Elmaleh-Bergès, Hélène Ogier de Baulny, Anne Lombès, Clémence Labasse, J. Wade Harper, P. Rustin, Norma B. Romero, Apolline Imbard, Abdelhamid Slama, Pauline Gaignard, Dominique Chrétien, Agnès Bourillon, Paule Bénit, Jean-François Benoist, Imen Dorboz, Claude Jardel, Department of Cell Biology [Boston, MA, USA], Harvard Medical School [Boston] (HMS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de biochimie-hormonologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Department of Pediatrics [Pittsburgh, USA], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE)-Children's Hospital of Pittsburgh of UPMC [Etats-Unis], Service de Biochimie [Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service de Radiologie [AP-HP Hôpital Robert Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Reference Center for Inborn Errors of Metabolism [AP-HP Hôpital Robert Debré], Bos, Mireille, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Harvard Medical School - HMS [Boston, USA], Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Promoting Research Oriented Towards Early Cns Therapies ( PROTECT ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Association française contre les myopathies ( AFM-Téléthon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), University of Pittsburgh School of Medicine [USA]-Children's Hospital of Pittsburgh of UPMC [Etats-Unis], and Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre

Subjects
0301 basic medicine, Male, Respiratory chain, Biology (General), Genetics, MICOS complex, biology, General Neuroscience, Liver Diseases, General Medicine, Null allele, Cell biology, MICOS, mitochondrial disease, Medicine, Female, 3-methylglutaconic aciduria, liver disease, Human, QH301-705.5, Mitochondrial disease, Protein subunit, Science, Microbial Sensitivity Tests, General Biochemistry, Genetics and Molecular Biology, Mitochondrial Proteins, 03 medical and health sciences, Mitochondrial Encephalomyopathies, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cytochrome c oxidase, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Human Biology and Medicine, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, General Immunology and Microbiology, Siblings, Infant, Newborn, Membrane Proteins, Cell Biology, medicine.disease, QIL1, 030104 developmental biology, Mutation, biology.protein, early-onset fatal mitochondrial encephalopathy, Cristae formation, Research Advance
Abstract

Previously, we identified QIL1 as a subunit of mitochondrial contact site (MICOS) complex and demonstrated a role for QIL1 in MICOS assembly, mitochondrial respiration, and cristae formation critical for mitochondrial architecture (Guarani et al., 2015). Here, we identify QIL1 null alleles in two siblings displaying multiple clinical symptoms of early-onset fatal mitochondrial encephalopathy with liver disease, including defects in respiratory chain function in patient muscle. QIL1 absence in patients’ fibroblasts was associated with MICOS disassembly, abnormal cristae, mild cytochrome c oxidase defect, and sensitivity to glucose withdrawal. QIL1 expression rescued cristae defects, and promoted re-accumulation of MICOS subunits to facilitate MICOS assembly. MICOS assembly and cristae morphology were not efficiently rescued by over-expression of other MICOS subunits in patient fibroblasts. Taken together, these data provide the first evidence of altered MICOS assembly linked with a human mitochondrial disease and confirm a central role for QIL1 in stable MICOS complex formation.

Published
2016

6. Author response: QIL1 mutation causes MICOS disassembly and early onset fatal mitochondrial encephalopathy with liver disease

Author

Clémence Labasse, J. Wade Harper, Anne Lombès, Jean-François Benoist, Mylène Gilleron, Monique Elmaleh-Bergès, Emmanuelle Lacène, Hélène Ogier de Baulny, Eric S. Goetzman, P. Rustin, Manuel Schiff, Joao A. Paulo, Norma B. Romero, Paule Bénit, Abdelhamid Slama, Dominique Chrétien, Agnès Bourillon, Virginia Guarani, Imen Dorboz, Pauline Gaignard, Claude Jardel, and Apolline Imbard

Subjects
Liver disease, business.industry, Mutation (genetic algorithm), Immunology, medicine, Mitochondrial encephalopathy, medicine.disease, business, Early onset
Published
2016

7. Severe respiratory complex III defect prevents liver adaptation to prolonged fasting

Author

Pierre Lesimple, Neji Tebib, Tim M. Strom, Thomas Meitinger, Holger Prokisch, Guy Touati, Anne Lombès, Claude Jardel, Mylène Gilleron, Tobias B. Haack, Caroline L’hermitte-Stead, Hélène Ogier de Baulny, Sandrine Filaut, Laura S. Kremer, Hatem Azzouz, Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital La Rabta [Tunis], Service de neurologie pédiatrique et maladies métaboliques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service Gastroentérologie, hépatologie nutrition, diabétologie et maladies héréditaires du métabolisme pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), This work was supported by grants from the FRM (Fondation pour la Recherche Médicale) grant DPM20121125550 to AL, from the Association Française contre les Myopathies (AFM) to AL and Association contre les Maladies Mitochondriales (AMMi) to AL, German Bundesministerium für Bildung und Forschung (BMBF) through funding of the E-Rare project GENOMIT (01GM1207) (TM, HP), German Network for mitochondrial disorders (mitoNET, 01GM1113C) (TM, HP)., Lombès, Anne, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hépatologie et Maladies Héréditaires du Métabolisme, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Centre de référence commun pour les maladies héréditaires du métabolisme, Technische Universität München [München] ( TUM ) -German Research Center for Environmental Health-Helmholtz-Zentrum München ( HZM ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Hôpital La Rabta [Tunis), and Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 )

Subjects
0301 basic medicine, LYRM7, fasting, hyperammonemia, MTO1, Biology, Bioinformatics, Article, Mitochondrial Proteins, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, respiratory complex III, medicine, Mitochondrial oxidative phosphorylation pathway, Humans, Exome, Genetics, Sanger sequencing, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Hepatology, Respiration, Homozygote, liver failure, High-Throughput Nucleotide Sequencing, Hyperammonemia, medicine.disease, Adaptation, Physiological, 3. Good health, Complementation, 030104 developmental biology, hypoglycemia, Liver, Lactic acidosis, Coenzyme Q – cytochrome c reductase, symbols, functional complementation, Liver function, Severe lactic acidosis, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Next generation sequencing approaches have tremendously improved the diagnosis of rare genetic diseases. It may however be faced with difficult clinical interpretation of variants. Inherited enzymatic diseases provide an invaluable possibility to evaluate the function of the defective enzyme in human cell biology. This is the case for respiratory complex III, which has 11 structural subunits and requires several assembly factors. An important role of complex III in liver function is suggested by its frequent impairment in human cases of genetic complex III defects.We report the case of a child with complex III defect and acute liver dysfunction with lactic acidosis, hypoglycemia, and hyperammonemia. Mitochondrial activities were assessed in liver and fibroblasts using spectrophotometric assays. Genetic analysis was done by exome followed by Sanger sequencing. Functional complementation of defective fibroblasts was performed using lentiviral transduction followed by enzymatic analyses and expression assays.Homozygous, truncating, mutations in LYRM7 and MTO1, two genes encoding essential mitochondrial proteins were found. Functional complementation of the complex III defect in fibroblasts demonstrated the causal role of LYRM7 mutations. Comparison of the patient's clinical history to previously reported patients with complex III defect due to nuclear DNA mutations, some actually followed by us, showed striking similarities allowing us to propose common pathophysiology.Profound complex III defect in liver does not induce actual liver failure but impedes liver adaptation to prolonged fasting leading to severe lactic acidosis, hypoglycemia, and hyperammonemia, potentially leading to irreversible brain damage.The diagnosis of rare genetic disease has been tremendously accelerated by the development of high throughput sequencing technology. In this paper we report the investigations that have led to identify LYRM7 mutations causing severe hepatic defect of respiratory complex III. Based on the comparison of the patient's phenotype with other cases of complex III defect, we propose that profound complex III defect in liver does not induce actual liver failure but impedes liver adaptation to prolonged fasting.

Published
2016

8. Unsolved issues related to human mitochondrial diseases

Author

Mylène Gilleron, Claude Jardel, Christine Bellanné-Chantelot, Anne Lombès, Karine Auré, Lombès, Anne, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), This work was supported by grants from the Association Française contre les Myopathies (AFM), from the Association contre les Maladies Mitochondriales (AMMi), and from the Fondation pour la Recherche Médicale (FRM) to AL., Institut Cochin (UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Pitié-Salpêtrière [APHP], Centre de Génétique moléculaire et chromosomique, and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
human diseases, Mitochondrial DNA, Mitochondrial Diseases, Genotype, Mutant, oxidative phosphorylation, Inheritance Patterns, Mitosis, tissue specificity, Biology, medicine.disease_cause, Biochemistry, Human mitochondrial genetics, Chimerism, DNA, Mitochondrial, Mitochondrial Proteins, Genetic Heterogeneity, medicine, Animals, Humans, heteroplasmy, Genetics, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Mutation, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Phenotype, Heteroplasmy, Mitochondria, mitochondrial fusion, Gene Expression Regulation, Organ Specificity
Abstract

19 pages; International audience; : Human mitochondrial diseases, defined as the diseases due to a mitochondrial oxidative phosphorylation defect, represent a large group of very diverse diseases with respect to phenotype and genetic causes. They present with many unsolved issues, the comprehensive analysis of which is beyond the scope of this review. We here essentially focus on the mechanisms underlying the diversity of targeted tissues, which is an important component of the large panel of these diseases phenotypic expression. The reproducibility of genotype/phenotype expression, the presence of modifying factors, and the potential causes for the restricted pattern of tissular expression are reviewed. Special emphasis is made on heteroplasmy, a specific feature of mitochondrial diseases, defined as the coexistence within the cell of mutant and wild type mitochondrial DNA molecules. Its existence permits unequal segregation during mitoses of the mitochondrial DNA populations and consequently heterogeneous tissue distribution of the mutation load. The observed tissue distributions of recurrent human mitochondrial DNA deleterious mutations are diverse but reproducible for a given mutation demonstrating that the segregation is not a random process. Its extent and mechanisms remain essentially unknown despite recent advances obtained in animal models.

Published
2013

9. NADPH oxidases participate to doxorubicin-induced cardiac myocyte apoptosis

Author

Mylène Gilleron, Remi Neviere, Steve Lancel, Jessica Franczak, David Montaigne, and Xavier Marechal

Subjects
Population, Biophysics, Apoptosis, Pharmacology, medicine.disease_cause, Biochemistry, chemistry.chemical_compound, medicine, Animals, Doxorubicin, Myocytes, Cardiac, education, Molecular Biology, chemistry.chemical_classification, education.field_of_study, Reactive oxygen species, NADPH oxidase, Antibiotics, Antineoplastic, biology, Superoxide, NADPH Oxidases, Cell Biology, Rats, Enzyme Activation, chemistry, Apocynin, biology.protein, Reactive Oxygen Species, Oxidative stress, Myoblasts, Cardiac, medicine.drug
Abstract

Cumulative doses of doxorubicin, a potent anticancer drug, lead to serious myocardial dysfunction. Numerous mechanisms including apoptosis have been proposed to account for its cardiotoxicity. Cardiac apoptosis induced by doxorubicin has been related to excessive reactive oxygen species production by the mitochondrial NADH dehydrogenase. Here, we explored whether doxorubicin treatment activates other superoxide anion generating systems such as the NADPH oxidases, membrane-embedded flavin-containing enzymes, and whether the subsequent oxidative stress contributes to apoptosis. We showed that doxorubicin treatment of rat cardiomyoblasts H9c2 triggers increases in caspase-3 like activity and hypoploid cells, both common features of apoptosis. Doxorubicin exposure also leads to a rapid superoxide production through NADPH oxidase activation. Inhibition of these enzymes using diphenyliodonium and apocynin reduces doxorubicin-induced reactive oxygen species production, caspase-3 like activity and sub-G1 cell population. In conclusion, NADPH oxidases participate to doxorubicin-induced cardiac apoptosis.

Published
2009

10. Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE

Author

Didier Périsse, Clement A. Gautier, Guillaume Huguet, Anne Faudet, Claudine Laurent, C Dupuits, Christopher Gillberg, Delphine Bouteiller, Cyril Mignot, Delphine Héron, Sandra Whalen, David Cohen, Mylène Gilleron, Marion Leboyer, Boris Keren, Thomas Bourgeron, Marion Gérard, Alexis Brice, C. Depienne, Alexandra Afenjar, Agnès Rastetter, Foudil Lamari, Richard Delorme, Aurélia Jacquette, Caroline Nava, S Caillet, and Bruno Leheup

Subjects
Adult, Male, Candidate gene, TMLHE, Nonsense mutation, Biology, medicine.disease_cause, Polymerase Chain Reaction, Mixed Function Oxygenases, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Genes, X-Linked, medicine, Humans, Missense mutation, Exome, Family, Sex Distribution, Child, Genetic Association Studies, Biological Psychiatry, X chromosome, 030304 developmental biology, Genetics, Chromosomes, Human, X, 0303 health sciences, Mutation, carnitine, Autism spectrum disorders, medicine.disease, Psychiatry and Mental health, Child Development Disorders, Pervasive, male excess, Case-Control Studies, chromosome X, Autism, Original Article, next-generation sequencing, Female, 030217 neurology & neurosurgery
Abstract

The striking excess of affected males in autism spectrum disorders (ASD) suggests that genes located on chromosome X contribute to the etiology of these disorders. To identify new X-linked genes associated with ASD, we analyzed the entire chromosome X exome by next-generation sequencing in 12 unrelated families with two affected males. Thirty-six possibly deleterious variants in 33 candidate genes were found, including PHF8 and HUWE1, previously implicated in intellectual disability (ID). A nonsense mutation in TMLHE, which encodes the ɛ-N-trimethyllysine hydroxylase catalyzing the first step of carnitine biosynthesis, was identified in two brothers with autism and ID. By screening the TMLHE coding sequence in 501 male patients with ASD, we identified two additional missense substitutions not found in controls and not reported in databases. Functional analyses confirmed that the mutations were associated with a loss-of-function and led to an increase in trimethyllysine, the precursor of carnitine biosynthesis, in the plasma of patients. This study supports the hypothesis that rare variants on the X chromosome are involved in the etiology of ASD and contribute to the sex-ratio disequilibrium.

Published
2012

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