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C9orf72 regulates energy homeostasis by stabilizing mitochondrial complex I assembly.
Wang, Tao; Liu, Honghe; Itoh, Kie; Oh, Sungtaek; Zhao, Liang; Murata, Daisuke; Sesaki, Hiromi; Hartung, Thomas; Na, Chan Hyun; Wang, Jiou.
Afiliación
  • Wang T; Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Liu H; Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Itoh K; Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Oh S; Department of Neurology, Institute for Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Zhao L; Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Murata D; Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Sesaki H; Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Hartung T; Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Na CH; Department of Neurology, Institute for Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Wang J; Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: jiouw@jhmi.edu.
Cell Metab ; 33(3): 531-546.e9, 2021 03 02.
Article en En | MEDLINE | ID: mdl-33545050
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Complejo I de Transporte de Electrón / Metabolismo Energético / Proteína C9orf72 Límite: Animals / Humans Idioma: En Revista: Cell Metab Asunto de la revista: METABOLISMO Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Complejo I de Transporte de Electrón / Metabolismo Energético / Proteína C9orf72 Límite: Animals / Humans Idioma: En Revista: Cell Metab Asunto de la revista: METABOLISMO Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos