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oai:repisalud.isciii.es:20.500.12105/202462024-11-29T00:31:11Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16967

00925njm 22002777a 4500 dc Genin, Emmanuelle C author Plutino, Morgane author Bannwarth, Sylvie author Villa, Elodie author Cisneros-Barroso, Eugenia author Roy, Madhuparna author Ortega-Vila, Bernardo author Fragaki, Konstantina author Lespinasse, Francoise author Pinero-Martos, Estefania author Auge, Gaelle author Moore, David author Burte, Florence author Lacas-Gervais, Sandra author Kageyama, Yusuke author Itoh, Kie author Yu-Wai-Man, Patrick author Sesaki, Hiromi author Ricci, Jean-Ehrland author Vives-Bauza, Cristofol author Paquis-Flucklinger, Veronique author 2016-01 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. Genin 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. 10.15252/emmm.201505496 1757-4684 1757-4676 Embo Molecular Medicine http://hdl.handle.net/20.500.13003/10562 26666268 L607342925 2-s2.0-84956738385 http://hdl.handle.net/20.500.12105/20246 368135800006 CHCHD10 Mitochondria Mitochondrial disease Motor neuron disease mtDNA instability CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis