C9orf72 regulates energy homeostasis by stabilizing mitochondrial complex I assembly

Tao Wang; Honghe Liu; Kie Itoh; Sungtaek Oh; Liang Zhao; Daisuke Murata; Hiromi Sesaki; Thomas Hartung; Chan Hyun Na; Jiou Wang

doi:10.1016/j.cmet.2021.01.005

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.

Authors

Tao Wang¹, Honghe Liu¹, Kie Itoh², Sungtaek Oh³, Liang Zhao⁴, Daisuke Murata², Hiromi Sesaki², Thomas Hartung⁴, Chan Hyun Na³, Jiou Wang⁵

Affiliations

¹ 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.
² Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
³ Department of Neurology, Institute for Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
⁴ Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
⁵ 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.

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.

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding