Loss of CHCHD2 and CHCHD10 activates OMA1 peptidase to disrupt mitochondrial cristae phenocopying patient mutations
| العنوان: | Loss of CHCHD2 and CHCHD10 activates OMA1 peptidase to disrupt mitochondrial cristae phenocopying patient mutations |
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| المؤلفون: | Mario K Shammas, Beverly P Wu, Shiori Sekine, Diana Nguyen, Joanna Poulton, Derek P. Narendra, Xiaoping Huang, Yi-Ting Liu, Danielle A. Springer, Eszter Dombi |
| المصدر: | Hum Mol Genet |
| بيانات النشر: | Oxford University Press (OUP), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Mutant, Mitochondrion, Biology, complex mixtures, Mitochondrial Proteins, Pathogenesis, Mice, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Animals, Humans, Integrated stress response, Genetic Predisposition to Disease, Amyotrophic lateral sclerosis, Myopathy, Molecular Biology, Genetics (clinical), 030304 developmental biology, Mice, Knockout, Crista ampullaris, 0303 health sciences, Amyotrophic Lateral Sclerosis, Parkinson Disease, General Medicine, medicine.disease, Mitochondria, Cell biology, DNA-Binding Proteins, Disease Models, Animal, Frontotemporal Dementia, Mutation, Metalloproteases, lipids (amino acids, peptides, and proteins), General Article, medicine.symptom, Cardiomyopathies, 030217 neurology & neurosurgery, Cytokinesis, HeLa Cells, Transcription Factors |
| الوصف: | 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. |
| تدمد: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddaa077 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5fa57d37a8d74955b9d902ce8e77d052 https://doi.org/10.1093/hmg/ddaa077 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....5fa57d37a8d74955b9d902ce8e77d052 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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| DOI: | 10.1093/hmg/ddaa077 |