The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction

J Biol Chem. 2018 Apr 27;293(17):6517-6529. doi: 10.1074/jbc.RA117.001073. Epub 2018 Mar 14.


Coiled-coil-helix-coiled-coil-helix domain-containing 10 (CHCHD10) and CHCHD2 (MNRR1) are homologous proteins with 58% sequence identity and belong to the twin CX9C family of proteins that mediate cellular stress responses. Despite the identification of several neurodegeneration-associated mutations in the CHCHD10 gene, few studies have assessed its physiological role. Here, we investigated CHCHD10's function as a regulator of oxidative phosphorylation in the mitochondria and the nucleus. We show that CHCHD10 copurifies with cytochrome c oxidase (COX) and up-regulates COX activity by serving as a scaffolding protein required for MNRR1 phosphorylation, mediated by ARG (ABL proto-oncogene 2, nonreceptor tyrosine kinase (ABL2)). The CHCHD10 gene was maximally transcribed in cultured cells at 8% oxygen, unlike MNRR1, which was maximally expressed at 4%, suggesting a fine-tuned oxygen-sensing system that adapts to the varying oxygen concentrations in the human body under physiological conditions. We show that nuclear CHCHD10 protein down-regulates the expression of genes harboring the oxygen-responsive element (ORE) in their promoters by interacting with and augmenting the activity of the largely uncharacterized transcriptional repressor CXXC finger protein 5 (CXXC5). We further show that two genetic CHCHD10 disease variants, G66V and P80L, in the mitochondria exhibit faulty interactions with MNRR1 and COX, reducing respiration and increasing reactive oxygen species (ROS), and in the nucleus abrogating transcriptional repression of ORE-containing genes. Our results reveal that CHCHD10 positively regulates mitochondrial respiration and contributes to transcriptional repression of ORE-containing genes in the nucleus, and that genetic CHCHD10 variants are impaired in these activities.

Keywords: cell stress; cytochrome c oxidase (Complex IV); energy metabolism; hypoxia; mitochondria; mitochondrial disease; neurodegenerative disease; scaffolding protein; transcriptional regulator.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Cell Nucleus / pathology
  • DNA-Binding Proteins
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Oxygen Consumption
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Mas
  • Reactive Oxygen Species / metabolism
  • Response Elements*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic*


  • CHCHD10 protein, human
  • CHCHD2 protein, human
  • CXXC5 protein, human
  • Carrier Proteins
  • DNA-Binding Proteins
  • MAS1 protein, human
  • Mitochondrial Proteins
  • Proto-Oncogene Mas
  • Reactive Oxygen Species
  • Transcription Factors
  • ARG tyrosine kinase
  • Protein-Tyrosine Kinases