C9orf72 regulates energy homeostasis by stabilizing mitochondrial complex I assembly

Wang Tao; Liu Honghe; Itoh KieOh SungtaekZhao LiangMurata DaisukeSesaki HiromiHartung ThomasNa Chan HyunWang Jiou

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C9orf72 regulates energy homeostasis by stabilizing mitochondrial complex I assembly

机译：C9orf72 regulates energy homeostasis by stabilizing mitochondrial complex I assembly

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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 amitochondrial 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.

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《Cell metabolism》 |2021年第3期|531-546|共25页
作者
Wang Tao; Liu Honghe; Itoh KieOh SungtaekZhao LiangMurata DaisukeSesaki HiromiHartung ThomasNa Chan HyunWang Jiou;
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Johns Hopkins Med Inst, Sch Med, Inst Cell Engn, Dept Neurosci, Baltimore, MD 21205 USA;

Johns Hopkins Med Inst, Bloomberg Sch Publ Hlth, Dept Environm Hlth & Engn, Baltimore, MD 21205 USA;

Johns Hopkins Med Inst, Sch Med, Dept Cell Biol, Baltimore, MD 21205 USAJohns Hopkins Med Inst, Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA;

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正文语种英语
中图分类内分泌腺疾病及代谢病;
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C9orf72 regulates energy homeostasis by stabilizing mitochondrial complex I assembly

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