PT  - JOURNAL ARTICLE
AU  - Maxence Le Vasseur
AU  - Jonathan R. Friedman
AU  - Marco Jost
AU  - Jiawei Xu
AU  - Justin Yamada
AU  - Martin Kampmann
AU  - Max A. Horlbeck
AU  - Michelle R. Salemi
AU  - Brett S. Phinney
AU  - Jonathan S. Weissman
AU  - Jodi Nunnari
TI  - Genome-wide CRISPRi screening identifies OCIAD1 as a prohibitin client and regulatory determinant of mitochondrial Complex III assembly in human cells
AID  - 10.1101/2021.02.16.431450
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.02.16.431450
4099  - http://biorxiv.org/content/early/2021/02/17/2021.02.16.431450.short
4100  - http://biorxiv.org/content/early/2021/02/17/2021.02.16.431450.full
AB  - 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 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.Competing Interest StatementJSW consults for and holds equity in KSQ Therapeutics, Maze Therapeutics, and Tenaya Therapeutics. JSW is a venture partner at 5AM Ventures and a member of the Amgen Scientific Advisory Board. MJ consults for Maze Therapeutics.