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

Abstract

Dominant mutations in the mitochondrial paralogs coiled-helix-coiled-helix (CHCHD) domain 2 (C2) and CHCHD10 (C10) were recently identified as causing Parkinson’s disease and amyotrophic lateral sclerosis/frontotemporal dementia/myopathy, respectively. The mechanism by which they disrupt mitochondrial cristae, however, has been uncertain. Using the first C2/C10 double knockout (DKO) mice, we report that C10 pathogenesis and the normal function of C2/C10 are intimately linked. Similar to patients with C10 mutations, we found that C2/C10 DKO mice have disrupted mitochondrial cristae, because of cleavage of the mitochondrial-shaping protein long form of OPA1 (L-OPA1) by the stress-induced peptidase OMA1. OMA1 was found to be activated similarly in affected tissues of mutant C10 knock-in (KI) mice, demonstrating that L-OPA1 cleavage is a novel mechanism for cristae abnormalities because of both C10 mutation and C2/C10 loss. Using OMA1 activation as a functional assay, we found that C2 and C10 are partially functionally redundant, and some but not all disease-causing mutations have retained activity. Finally, C2/C10 DKO mice partially phenocopied mutant C10 KI mice with the development of cardiomyopathy and activation of the integrated mitochondrial integrated stress response in affected tissues, tying mutant C10 pathogenesis to C2/C10 function.

Early death of ALS-linked CHCHD10-R15L transgenic mice with central nervous system, skeletal muscle, and cardiac pathology

“…Furthermore, the axonal swelling pathology and cardiac pathology observed in the CHCHD10-R15L transgenic lines are absent from the Chchd10-KO mice ( Figures S12 D–S12G). A recent report describing Chchd10/Chchd2 double KO mice describes vacuolar pathology and abnormal mitochondrial cristae structure in the heart along with echocardiographic deficits resulting in early death of the mice ( Liu et al., 2020b ). The discordance between the single and double KO mice suggests Chchd2 compensates for the lack of Chchd10 in the single KO mice.…”

“…Our data warrant consideration to cardiac dysfunction being given to patients with a CHCHD10 p.R15L mutation. Additional evidence that mutant CHCHD10 impacts upon multiple tissues is provided by three independently reported knock-in mouse models of the CHCHD10 p.S59L mutation ( Anderson et al., 2019 ; Genin et al., 2019 ; Liu et al., 2020b ). This mutation was identified in patients with complex and varying phenotypes including myopathy, ataxia, cognitive impairment, motor neuron disease, and deafness, as well as a singleton ALS-FTD case ( Bannwarth et al., 2014 ).…”

“…Short-term studies of Chchd10-KO mice do not reveal a striking phenotype ( Burstein et al., 2018 ; Liu et al., 2020b ; Anderson et al., 2019 ). However, Chchd10/Chchd2 double KO mice display a variety of phenotypes including vacuolar pathology and abnormal mitochondrial cristae structure in the heart along with echocardiographic deficits ( Liu et al., 2020b ). Furthermore, the double KO mice display increased OMA1 cleavage of OPA1 and upregulation of the mitochondrial integrated stress response.…”

Reduced erythrocytic CHCHD2 mRNA is associated with brain pathology of Parkinson’s disease

“…Additionally, knockout of CHCHD2 or CHCHD10 in human induced pluripotent stem cells led to increased proton leakage and respiration, as well as loss of synaptic function [ 11 ]. CHCHD2/CHCHD10 double knockout mice showed disrupted mitochondrial cristae [ 17 ].…”

A CHCHD10 variant causing ALS elicits an unfolded protein response through the IRE1/XBP1 pathway

“…Recently, two groups reported the activation of the ISR for the CHCHD10 variant p.S59L and the double knock-out of CHCHD10 and CHCHD2 in mouse models (Anderson et al, 2019). CHCHD10 p.S59L accumulated as protein aggregates in a knock-in (KI) mouse and thereby induced the activation of mTORC1, the increase of transcription factors specific for the stress response, the secretion of metabolic cytokines FGF21 and GDF15, the upregulation of the serine and one-carbon metabolism, and the downregulation of the respiratory chain complexes (Anderson et al, 2019, Liu, Huang et al, 2020. Although the p.S59L CHCHD10 variant was proposed to act through a dominant gain of function mechanism (Anderson et al, 2019), and the double-knock-out through a complete loss of function, both models showed activation of the ISR.…”