C9orf72 regulates energy homeostasis by stabilizing mitochondrial complex I assembly

Cell Metab. 2021 Mar 2;33(3):531-546.e9. doi: 10.1016/j.cmet.2021.01.005. Epub 2021 Feb 4.


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.

Keywords: ALS; C9orf72; FTD; OXPHOS; TIMMDC1; complex I; mitochondrial import; mitochondrion; neurodegeneration; oxidative phosphorylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ATP-Dependent Proteases / metabolism
  • ATPases Associated with Diverse Cellular Activities / metabolism
  • Animals
  • Apoptosis Inducing Factor / antagonists & inhibitors
  • Apoptosis Inducing Factor / genetics
  • Apoptosis Inducing Factor / metabolism
  • C9orf72 Protein / antagonists & inhibitors
  • C9orf72 Protein / genetics
  • C9orf72 Protein / metabolism*
  • Cell Line
  • Cell Survival
  • Electron Transport Complex I / chemistry
  • Electron Transport Complex I / metabolism*
  • Energy Metabolism / physiology*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism
  • Mitochondrial Precursor Protein Import Complex Proteins / antagonists & inhibitors
  • Mitochondrial Precursor Protein Import Complex Proteins / genetics
  • Mitochondrial Precursor Protein Import Complex Proteins / metabolism
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Oxidative Phosphorylation
  • RNA Interference
  • RNA, Small Interfering / metabolism


  • Apoptosis Inducing Factor
  • C9orf72 Protein
  • Chchd4 protein, mouse
  • Mitochondrial Precursor Protein Import Complex Proteins
  • RNA, Small Interfering
  • ATP-Dependent Proteases
  • Afg3l2 protein, mouse
  • ATPases Associated with Diverse Cellular Activities
  • Electron Transport Complex I