title: CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis.
abstract: CHCHD10-related diseases include mitochondrial DNA instability disorder, frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) clinical spectrum, late-onset spinal motor neuropathy (SMAJ), and Charcot-Marie-Tooth disease type 2 (CMT2). Here, we show that CHCHD10 resides with mitofilin, CHCHD3 and CHCHD6 within the "mitochondrial contact site and cristae organizing system" (MICOS) complex. CHCHD10 mutations lead to MICOS complex disassembly and loss of mitochondrial cristae with a decrease in nucleoid number and nucleoid disorganization. Repair of the mitochondrial genome after oxidative stress is impaired in CHCHD10 mutant fibroblasts and this likely explains the accumulation of deleted mtDNA molecules in patient muscle. CHCHD10 mutant fibroblasts are not defective in the delivery of mitochondria to lysosomes suggesting that impaired mitophagy does not contribute to mtDNA instability. Interestingly, the expression of CHCHD10 mutant alleles inhibits apoptosis by preventing cytochrome c release.
authors.affiliation: IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, Nice Cedex 2, France.
authors.forename: Emmanuelle C
authors.initials: EC
authors.lastname: Genin
authors.affiliation: IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, Nice Cedex 2, France.
authors.forename: Morgane
authors.initials: M
authors.lastname: Plutino
authors.affiliation: IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, Nice Cedex 2, France Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, Nice Cedex 2, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bannwarth
authors.affiliation: INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe "contrôle métabolique des morts cellulaires", Nice Sophia-Antipolis University, Nice Cedex 2, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Villa
authors.affiliation: Research Health Institute of Palma (IdISPa), Research Unit, Son Espases University Hospital, Palma de Mallorca, Spain.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Cisneros-Barroso
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Madhuparna
authors.initials: M
authors.lastname: Roy
authors.affiliation: Research Health Institute of Palma (IdISPa), Research Unit, Son Espases University Hospital, Palma de Mallorca, Spain.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Ortega-Vila
authors.affiliation: IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, Nice Cedex 2, France Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, Nice Cedex 2, France.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Fragaki
authors.affiliation: IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, Nice Cedex 2, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Lespinasse
authors.affiliation: Research Health Institute of Palma (IdISPa), Research Unit, Son Espases University Hospital, Palma de Mallorca, Spain.
authors.forename: Estefania
authors.initials: E
authors.lastname: Pinero-Martos
authors.affiliation: IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, Nice Cedex 2, France Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, Nice Cedex 2, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Augé
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life Newcastle University, Newcastle upon Tyne, UK Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: David
authors.initials: D
authors.lastname: Moore
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life Newcastle University, Newcastle upon Tyne, UK Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: Florence
authors.initials: F
authors.lastname: Burté
authors.affiliation: Joint Center for Applied Electron Microscopy, Nice Sophia-Antipolis University, Nice Cedex 2, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lacas-Gervais
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kageyama
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Kie
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life Newcastle University, Newcastle upon Tyne, UK Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Yu-Wai-Man
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sesaki
authors.affiliation: INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe "contrôle métabolique des morts cellulaires", Nice Sophia-Antipolis University, Nice Cedex 2, France.
authors.forename: Jean-Ehrland
authors.initials: JE
authors.lastname: Ricci
authors.affiliation: Research Health Institute of Palma (IdISPa), Research Unit, Son Espases University Hospital, Palma de Mallorca, Spain.
authors.forename: Cristofol
authors.initials: C
authors.lastname: Vives-Bauza
authors.affiliation: IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, Nice Cedex 2, France Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, Nice Cedex 2, France paquis@hermes.unice.fr.
authors.forename: Véronique
authors.initials: V
authors.lastname: Paquis-Flucklinger
mesh_terms: D000483:Alleles; D017209:Apoptosis / Q000235:genetics*; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000032:analysis / Q000378:metabolism; D054629:Genome, Mitochondrial; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008247:Lysosomes / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C554426:CHCHD10 protein, human; C521110:CHCHD3 protein, human; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D045304:Cytochromes c; D006861:Hydrogen Peroxide
keywords: CHCHD10; mitochondria; mitochondrial disease; motor neuron disease; mtDNA instability