Loss of CHCHD2 and CHCHD10 activates OMA1 peptidase to disrupt mitochondrial cristae phenocopying patient mutations in vivo

Dominant mutations in the mitochondrial paralogs CHCHD2 (C2) and CHCHD10 (C10) were recently identified as causing Parkinsons disease and ALS/FTD/myopathy, respectively. Disruption of mitochondrial cristae has been observed in mutant C10 patient tissues and animal models, but the mechanism for this disruption remains controversial. Additionally, C10 patient mutant knock-in (KI) mice were recently reported to activate a mitochondrial integrated stress response (mt-ISR) and develop cardiomyopathy not seen in C10 knockout (KO) mice, calling into question whether mutant C10 pathogenesis is related to C2/C10 normal function or purely toxic gain of function. Here, using the first C2/10 double knockout (DKO) mice, we report that C10 pathogenesis and the normal function of C2/10 are intimately linked. Similar to patients with C10 mutations, we found that C2/10 DKO mice (but not either single KO mice) have disrupted mitochondrial cristae, due to cleavage of the mitochondrial shaping protein L-OPA1 by the stress-induced peptidase OMA1. OMA1 was found to be activated similarly in affected tissues of mutant C10 KI mice, demonstrating that L-OPA1 cleavage is a novel mechanism for cristae abnormalities due to both C10 mutation and C2/C10 loss, and that OMA1, a driver of neurodegeneration in other contexts, may be a therapeutic target. Finally, C2/10 DKO mice partially phenocopied mutant C10 KI mice with the development of cardiomyopathy and activation of the mt-ISR in affected tissues, tying mutant C10 pathogenesis to C2/C10 function.