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

EMBO Mol Med. 2016 Jan 1;8(1):58-72. doi: 10.15252/emmm.201505496.


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.

Keywords: CHCHD10; mitochondria; mitochondrial disease; motor neuron disease; mtDNA instability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Apoptosis / genetics*
  • Cell Line
  • Cytochromes c / metabolism
  • DNA Repair / drug effects
  • DNA, Mitochondrial / analysis
  • DNA, Mitochondrial / metabolism
  • Genome, Mitochondrial*
  • HeLa Cells
  • Humans
  • Hydrogen Peroxide / toxicity
  • Lysosomes / metabolism
  • Membrane Potential, Mitochondrial
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / pathology
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism
  • Mutation
  • Oxidative Stress / drug effects
  • Real-Time Polymerase Chain Reaction


  • CHCHD10 protein, human
  • CHCHD3 protein, human
  • DNA, Mitochondrial
  • Mitochondrial Proteins
  • Cytochromes c
  • Hydrogen Peroxide