Genome-wide CRISPRi screening identifies OCIAD1 as a prohibitin client and regulatory determinant of mitochondrial Complex III assembly in human cells

eLife

Marco Jost¹  Martin Kampmann²  Justin Yamada³  Jonathan S Weissman³  Jodi Nunnari⁴  Jiawei Xu⁵  Brett S Phinney⁵  Michelle R Salemi⁶  Jonathan Friedman⁶  Max A Horlbeck⁶  Maxence Le Vasseur⁶ 

[1] Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, United States;Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, United States;Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, United States;Institute for Neurodegenerative Diseases and Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, United States;Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, United States;Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, Davis, United States;

关键词: mitochondria;    electron transport chain;    Complex III;    protease;    cytochrome c1;    prohibitin;   

DOI  :  10.7554/eLife.67624

来源: DOAJ

【 摘 要 】

Dysfunction of the mitochondrial electron transport chain (mETC) is a major cause of human mitochondrial diseases. To identify determinants of mETC function, we screened a genome-wide human CRISPRi library under oxidative metabolic conditions with selective inhibition of mitochondrial Complex III and identified ovarian carcinoma immunoreactive antigen (OCIA) domain-containing protein 1 (OCIAD1) as a Complex III assembly factor. We find that OCIAD1 is an inner mitochondrial membrane protein that forms a complex with supramolecular prohibitin assemblies. Our data indicate that OCIAD1 is required for maintenance of normal steady-state levels of Complex III and the proteolytic processing of the catalytic subunit cytochrome c1 (CYC1). In OCIAD1 depleted mitochondria, unprocessed CYC1 is hemylated and incorporated into Complex III. We propose that OCIAD1 acts as an adaptor within prohibitin assemblies to stabilize and/or chaperone CYC1 and to facilitate its proteolytic processing by the IMMP2L protease.

【 授权许可】

Unknown