CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis

Genin, Emmanuelle CPlutino, MorganeBannwarth, SylvieVilla, ElodieCisneros-Barroso, EugeniaRoy, MadhuparnaOrtega-Vila, BernardoFragaki, KonstantinaLespinasse, FrancoisePinero-Martos, EstefaniaAuge, GaelleMoore, DavidBurte, FlorenceLacas-Gervais, SandraKageyama, YusukeItoh, KieYu-Wai-Man, PatrickSesaki, HiromiRicci, Jean-EhrlandVives-Bauza, CristofolPaquis-Flucklinger, Veronique2024-07-092024-07-092016-01Genin EC, Plutino M, Bannwarth S, Villa E, Cisneros-Barroso E, Roy M, et al. CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis. EMBO Mol Med. 2016 Jan;8(1):58-72.1757-4676http://hdl.handle.net/20.500.13003/10562http://hdl.handle.net/20.500.12105/20246CHCHD10-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.enghttp://creativecommons.org/licenses/by/4.0/CHCHD10MitochondriaMitochondrial diseaseMotor neuron diseasemtDNA instabilityGenome, MitochondrialOxidative StressMitochondriaAllelesHumansCell LineHeLa CellsMitochondrial ProteinsReal-Time Polymerase Chain ReactionCytochromes cHydrogen PeroxideLysosomesDNA, MitochondrialDNA RepairMembrane Potential, MitochondrialMutationApoptosisMitochondrial DiseasesCHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosisresearch articleAttribution 4.0 International266662688158-7210.15252/emmm.2015054961757-4684Embo Molecular Medicineopen accessCitocromos cGenoma MitocondrialReparación del ADNApoptosisEnfermedades MitocondrialesProteínas MitocondrialesLínea CelularADN MitocondrialMutaciónAlelosCélulas HeLaPeróxido de HidrógenoLisosomasReacción en Cadena en Tiempo Real de la PolimerasaHumanosEstrés OxidativoPotencial de la Membrana MitocondrialMitocondrias2-s2.0-84956738385368135800006L607342925