CHCHD10-CHCHD2 complexes are required for mitochondrial respiration
Isabella R. Straub1,2, Alexandre Janer1,2, Woranontee Weraarpachai1,3, Lorne Zinman4, Janice Robertson5, Ekaterina Rogaeva5, Eric A. Shoubridge1,2
1Department of Human Genetics, McGill University, Montreal, Quebec, Canada
2Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
3Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
4Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
5Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
CHCHD10 and its paralogue CHCHD2 belong to a family of twin CX9C motif proteins, most of which localize to the intermembrane space of mitochondria. Dominant mutations in CHCHD10 cause amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), and mutations in CHCHD2 have been associated with Parkinson's disease, but the function of these proteins remains largely unknown. Here we show that the CHCHD10 and CHCHD2 form a high molecular weight complex of 220 kDa, as detected by Blue-Native PAGE, appear together in distinct foci by immunofluorescence analysis and can be quantitatively immunoprecipitated with antibodies against either protein. CHCHD10 and CHCHD2 levels increase markedly in control cells grown in galactose medium, a substrate that forces cells to synthesize all their ATP aerobically, a response that suggests a regulatory role of these proteins in stress conditions. The p.R15L CHCHD10 variant in ALS patient fibroblasts destabilizes the protein, leading to a defect in the assembly of complex I, impaired cellular respiration, mitochondrial hyperfusion, an increase in the steady-state level of CHCHD2, loss of the 220 kDa CHCHD10-CHCHD2 complex, and a severe proliferation defect on galactose; a phenotype that is phenocopied by a CRISPR-Cas9 CHCHD10 knockout cell line. Using a variety of “omics” approaches we are investigating further essential players in the CHCHD10-CHCHD2 regulatory pathway and their role in the pathogenesis of the two prominent neurodegenerative disorders, ALS and Parkinson's disease.