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

Emmanuelle Génin ,Patrick Yu‐Wai‐Man,Sandra Lacas‐Gervais,Yusuke Kageyama,Morgane Plutino,Kie Itoh,Gaëlle Augé,Sylvie Bannwarth,Konstantina Fragaki,Elodie Villa,Hiromi Sesaki,Véronique Paquis‐Flucklinger,David Moore,Florence Burté,Madhuparna Roy,Françoise Lespinasse,Eugenia Cisneros-Barroso ,Cristòfol Vives-Bauzà ,Bernardo Ortega-Vila ,Jean-Ehrland Ricci ,Estefanía Piñero-Martos

doi:10.15252/emmm.201505496

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 cytochromec release.

Highlights

CHCHD10-related diseases include mitochondrial DNA instability disorder, frontotemporal dementia-amyotrophic lateral sclerosis (FTD-Amyotrophic lateral sclerosis (ALS)) clinical spectrum, late-onset spinal motor neuropathy (SMAJ), and Charcot–Marie–Tooth disease type 2 (CMT2)
Results in mouse brain demonstrated that CHCHD10 forms part of a multiprotein complex containing the inner membrane mitochondrial proteins mitofilin, CHCHD3, and CHCHD6 (Fig 1A)
Recent studies in yeast have identified the mitochondrial inner membrane organizing system (MINOS) complex, which is located within the inner mitochondrial membrane (IMM) (Von der Malsburg et al, 2011; Friedman et al, 2015)

Summary

Introduction

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). 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. The expression of CHCHD10 mutant alleles inhibits apoptosis by preventing cytochrome c release

Methods

Results

Conclusion