Cell Metabolism
Volume 33, Issue 3, 2 March 2021, Pages 531-546.e9
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Article
C9orf72 regulates energy homeostasis by stabilizing mitochondrial complex I assembly

https://doi.org/10.1016/j.cmet.2021.01.005Get rights and content
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Highlights

  • C9orf72 is imported into mitochondrial IMS through the AIFM1/CHCHD4 pathway

  • Mitochondrial C9orf72 is crucial for OXPHOS functions and energy metabolism

  • C9orf72 enables effective CI assembly by stabilizing TIMMDC1

  • C9orf72 haploinsufficiency impairs CI and OXPHOS functions in ALS/FTD patient cells

Summary

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

C9orf72
complex I
mitochondrion
oxidative phosphorylation
mitochondrial import
neurodegeneration
TIMMDC1
ALS
FTD
OXPHOS

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