C9orf72 regulates energy homeostasis by stabilizing mitochondrial complex I assembly
| Autor: | Daisuke Murata, Hong-he Liu, Sungtaek Oh, Chan Hyun Na, Jiou Wang, Kie Itoh, Tao Wang, Hiromi Sesaki, Thomas Hartung, Liang Zhao |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
AIFM1 Physiology Cell Survival Mitochondrion Energy homeostasis Oxidative Phosphorylation Article Cell Line 03 medical and health sciences Mice 0302 clinical medicine ATP-Dependent Proteases C9orf72 Mitochondrial Precursor Protein Import Complex Proteins medicine Translocase Animals Humans Prohibitin RNA Small Interfering Inner mitochondrial membrane Molecular Biology Mice Knockout Electron Transport Complex I biology C9orf72 Protein Chemistry Neurodegeneration Apoptosis Inducing Factor Neurodegenerative Diseases Cell Biology medicine.disease Cell biology Mitochondria Mice Inbred C57BL 030104 developmental biology biology.protein ATPases Associated with Diverse Cellular Activities RNA Interference Energy Metabolism 030217 neurology & neurosurgery |
| Zdroj: | Cell Metab |
| ISSN: | 1932-7420 |
| Popis: | The haploinsufficiency of C9orf72 is implicated in the most common forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the full spectrum of C9orf72 functions remains to be established. Here, we report that C9orf72 is a mitochondrial inner-membrane-associated protein regulating cellular energy homeostasis via its critical role in the control of oxidative phosphorylation (OXPHOS). The translocation of C9orf72 from the cytosol to the inter-membrane space is mediated by the redox-sensitive AIFM1/CHCHD4 pathway. In mitochondria, C9orf72 specifically stabilizes translocase of inner mitochondrial membrane domain containing 1 (TIMMDC1), a crucial factor for the assembly of OXPHOS complex I. C9orf72 directly recruits the prohibitin complex to inhibit the m-AAA protease-dependent degradation of TIMMDC1. The mitochondrial complex I function is impaired in C9orf72-linked ALS/FTD patient-derived neurons. These results reveal a previously unknown function of C9orf72 in mitochondria and suggest that defective energy metabolism may underlie the pathogenesis of relevant diseases. |
| Databáze: | OpenAIRE |
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