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

EMBO Molecular Medicine

Emmanuelle C Genin⁴  Morgane Plutino⁴  Sylvie Bannwarth⁴  Elodie Villa³  Eugenia Cisneros-Barroso⁶  Madhuparna Roy²  Bernardo Ortega-Vila⁶  Konstantina Fragaki⁴  Françoise Lespinasse⁴  Estefania Pinero-Martos⁶  Gaëlle Augé⁴  David Moore¹  Florence Burté¹  Sandra Lacas-Gervais⁵  Yusuke Kageyama²  Kie Itoh²  Patrick Yu-Wai-Man¹  Hiromi Sesaki²  Jean-Ehrland Ricci³  Cristofol Vives-Bauza⁶ 

[1] Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, UK;Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA;INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe “contrôle métabolique des morts cellulaires”, Nice Sophia-Antipolis University, Nice Cedex 2, France;IRCAN, UMR CNRS 7284/INSERM U1081/UNS, School of Medicine, Nice Sophia-Antipolis University, Nice Cedex 2, France;Joint Center for Applied Electron Microscopy, Nice Sophia-Antipolis University, Nice Cedex 2, France;Research Health Institute of Palma (IdISPa), Research Unit, Son Espases University Hospital, Palma de Mallorca, Spain

关键词: CHCHD10;    mitochondria;    mitochondrial disease;    motor neuron disease;    mtDNA instability;   

DOI  :  10.15252/emmm.201505496

来源: Wiley

【 摘 要 】

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.

Synopsis

CHCHD10 is found to be part of the MICOS complex. Mutations in CHCHD10, previously associated with ALS, cause MICOS disassembly, loss of mitochondrial cristae, mitochondrial genome repair impairment after oxidative stress, and inhibition of apoptosis.

• CHCHD10 is found to be a component of the MICOS complex. CHCHD10 mutations disassemble the MICOS complex leading to loss of mitochondrial cristae junctions.
• Assembly of OXPHOS complexes is impaired leading to respiratory chain deficiency.
• Nucleoids are disorganized resulting in mtDNA repair impairment after oxidative stress.
• CHCHD10 mutations do not affect mitophagy.
• Expression of CHCHD10 mutant alleles prevents cytochrome c release and thus inhibits apoptosis via the caspase-dependent pathway.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

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