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

Autor: Emmanuelle C Genin, Morgane Plutino, Sylvie Bannwarth, Elodie Villa, Eugenia Cisneros‐Barroso, Madhuparna Roy, Bernardo Ortega‐Vila, Konstantina Fragaki, Françoise Lespinasse, Estefania Pinero‐Martos, Gaëlle Augé, David Moore, Florence Burté, Sandra Lacas‐Gervais, Yusuke Kageyama, Kie Itoh, Patrick Yu‐Wai‐Man, Hiromi Sesaki, Jean‐Ehrland Ricci, Cristofol Vives‐Bauza, Véronique Paquis‐Flucklinger
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 8, Iss 1, Pp 58-72 (2015)
Druh dokumentu: article
ISSN: 1757-4676
1757-4684
DOI: 10.15252/emmm.201505496
Popis: 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.
Databáze: Directory of Open Access Journals
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