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

Maxence Le Vasseur, Jonathan R. Friedman, Marco Jost, Jiawei Xu, Justin Yamada, Martin Kampmann, Max A. Horlbeck, Michelle R. Salemi, Brett S. Phinney, Jonathan S. Weissman, Jodi Nunnari
doi: https://doi.org/10.1101/2021.02.16.431450
Maxence Le Vasseur
1Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, CA, 95616, USA
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Jonathan R. Friedman
1Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, CA, 95616, USA
2Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
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Marco Jost
3Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, CA, 94158, USA
4Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, 94158, USA
5Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, CA, 94158, USA
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Jiawei Xu
1Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, CA, 95616, USA
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Justin Yamada
1Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, CA, 95616, USA
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Martin Kampmann
3Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, CA, 94158, USA
4Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, 94158, USA
6Institute for Neurodegenerative Diseases and Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, 94158, USA
7Chan-Zuckerberg Biohub, San Francisco, CA, 94158, USA
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Max A. Horlbeck
3Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, CA, 94158, USA
4Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, 94158, USA
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Michelle R. Salemi
8Proteomics Core Facility, University of California, Davis, CA 95616, USA
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Brett S. Phinney
8Proteomics Core Facility, University of California, Davis, CA 95616, USA
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Jonathan S. Weissman
3Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, CA, 94158, USA
4Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, 94158, USA
9Whitehead Institute, Cambridge, MA, USA
10Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
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Jodi Nunnari
1Department of Molecular and Cellular Biology, College of Biological Sciences, University of California, Davis, CA, 95616, USA
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  • For correspondence: jmnunnari@ucdavis.edu
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Abstract

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 Statement

JSW 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.

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Genome-wide CRISPRi screening identifies OCIAD1 as a prohibitin client and regulatory determinant of mitochondrial Complex III assembly in human cells
Maxence Le Vasseur, Jonathan R. Friedman, Marco Jost, Jiawei Xu, Justin Yamada, Martin Kampmann, Max A. Horlbeck, Michelle R. Salemi, Brett S. Phinney, Jonathan S. Weissman, Jodi Nunnari
bioRxiv 2021.02.16.431450; doi: https://doi.org/10.1101/2021.02.16.431450
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Genome-wide CRISPRi screening identifies OCIAD1 as a prohibitin client and regulatory determinant of mitochondrial Complex III assembly in human cells
Maxence Le Vasseur, Jonathan R. Friedman, Marco Jost, Jiawei Xu, Justin Yamada, Martin Kampmann, Max A. Horlbeck, Michelle R. Salemi, Brett S. Phinney, Jonathan S. Weissman, Jodi Nunnari
bioRxiv 2021.02.16.431450; doi: https://doi.org/10.1101/2021.02.16.431450

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