Dominant toxicity of ALS–FTD-associated CHCHD10 S59L is mediated by TDP-43 and PINK1

Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 () are a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia (ALS-FTD). To elucidate how mutations in induce disease, we generated a model of -mediated ALS-FTD. Expression of in caused gain-of-function toxicity in eyes, motor neurons, and muscles, in addition to mitochondrial defects in flies and HeLa cells. TDP-43 and PINK1 formed two axes, driving the mutant-dependent phenotypes. expression increased TDP-43 insolubility and mitochondrial translocation. Blocking mitochondrial translocation with a peptide inhibitor reduced -mediated toxicity. knockdown rescued -mediated phenotypes in and HeLa cells. The two PINK1 substrates mitofusin and mitofilin were genetic modifiers of this phenotype. Mitofusin agonists reversed the -induced phenotypes in and HeLa cells and increased ATP production in expressing with expanded GGGGCC repeats. Two peptides inhibitors of PINK1 mitigated the mitochondrial defects introduced by expression. These findings indicate that TDP-43 mitochondrial translocation and chronic activation of PINK1-mediated pathways by CHCHD10 generate dominant toxicity. Therefore, inhibiting PINK1 activity may provide a therapeutic strategy for -associated disease.