Objective: Characterization of novel of a novel CHCHD2 (C2) and CHCHD10 (C10) knockout mouse model.

Background: Dominant mutations in the mitochondrial paralogs CHCHD2 (C2) and CHCHD10 (C10) were recently identified as causing Parkinson’s disease and ALS/FTD/myopathy, respectively, and are associated with disruption of mitochondrial cristae in patient cells and tissues. Recently C10 knock-in (KI) mice were observed to develop a fatal cardiomyopathy associated with mitochondrial cristae abnormalities. The mechanism by which dominant C10 mutations cause mitochondrial cristae defects and their relationship to C2/C10 normal function, however, have been unclear.

Method: C2^-/-, C10^-/-, and C10^S59L/+ transgenic lines were produced using CRISPR/Cas9 endonuclease-mediated genome editing on the C57Bl6J background. CRISPR guide RNAs targeted exon 2 and 4 in mC10 and exon 1 and 4 in mC2 to generate breaks in DNA. All animal studies were approved by the Animal Care Use Committee at the NINDS intramural program.

Results: Here we report that C2/C10 double knockout (DKO) mice phenocopy C10 KI mice and C10 patients, developing both mitochondrial cristae defects and cardiomyopathy. We further identified activation of the stress-induced peptidase OMA1, leading to the excessive cleavage of L-OPA1, as the mechanism driving abnormalities in mitochondrial cristae. L-OPA1 processing defects could be restored by exogenous expression of either C2 or C10, demonstrating functional redundancy between the paralogs. Unexpectedly, overexpression of C2 or C10 also activated OMA1, mimicking C2/C10 loss of function. Thus, C2 and C10 levels must be maintained within a narrow range for balanced OPA1 processing. Activated OMA1 was likewise observed in tissues from C10 KI mice. We propose a model by which dominant mutations in C10 may change the effective concentration of C2/C10 thereby disrupting mitochondrial cristae and phenocopying C2/C10 loss of function.

Conclusion: Taken together our findings establish imbalanced OPA1 as the mechanism underlying cristae defects due to C2/C10 loss or mutation and tie mutant pathogenesis to C2/C10 physiologic function.

« Back to MDS Virtual Congress 2020

MDS Abstracts - https://www.mdsabstracts.org/abstract/loss-of-chchd2-and-chchd10-disrupts-mitochondrial-cristae-phenocopying-patient-mutations/