Defining mitochondrial protein functions through deep multiomic profiling

Jarred W. Rensvold, Evgenia Shishkova, Yuriy Sverchkov, Ian J. Miller, Arda Cetinkaya, Angela Pyle, Mateusz Manicki, Dain R. Brademan, Yasemin Alanay, Julian Raiman, Adam Jochem, Paul D. Hutchins, Sean R. Peters, Vanessa Linke, Katherine A. Overmyer, Austin Z. Salome, Alexander S. Hebert, Catherine E. Vincent, Nicholas W. Kwiecien, Matthew J. P. Rush, Michael S. Westphall, Mark Craven, Nurten A. Akarsu, Robert W. Taylor, Joshua J. Coon () and David J. Pagliarini ()
Additional contact information
Jarred W. Rensvold: Washington University School of Medicine
Evgenia Shishkova: National Center for Quantitative Biology of Complex Systems
Yuriy Sverchkov: University of Wisconsin–Madison
Ian J. Miller: National Center for Quantitative Biology of Complex Systems
Arda Cetinkaya: Hacettepe University
Angela Pyle: Newcastle University
Mateusz Manicki: Washington University School of Medicine
Dain R. Brademan: Morgridge Institute for Research
Yasemin Alanay: Hacettepe University
Julian Raiman: Birmingham Women’s and Children’s Hospital NHS Trust
Adam Jochem: Morgridge Institute for Research
Paul D. Hutchins: University of Wisconsin–Madison
Sean R. Peters: University of Wisconsin–Madison
Vanessa Linke: University of Wisconsin–Madison
Katherine A. Overmyer: Morgridge Institute for Research
Austin Z. Salome: University of Wisconsin–Madison
Alexander S. Hebert: National Center for Quantitative Biology of Complex Systems
Catherine E. Vincent: University of Wisconsin–Madison
Nicholas W. Kwiecien: National Center for Quantitative Biology of Complex Systems
Matthew J. P. Rush: University of Wisconsin–Madison
Michael S. Westphall: National Center for Quantitative Biology of Complex Systems
Mark Craven: University of Wisconsin–Madison
Nurten A. Akarsu: Hacettepe University
Robert W. Taylor: Newcastle University
Joshua J. Coon: Morgridge Institute for Research
David J. Pagliarini: Washington University School of Medicine

Nature, 2022, vol. 606, issue 7913, 382-388

Abstract: Abstract Mitochondria are epicentres of eukaryotic metabolism and bioenergetics. Pioneering efforts in recent decades have established the core protein componentry of these organelles1 and have linked their dysfunction to more than 150 distinct disorders2,3. Still, hundreds of mitochondrial proteins lack clear functions4, and the underlying genetic basis for approximately 40% of mitochondrial disorders remains unresolved5. Here, to establish a more complete functional compendium of human mitochondrial proteins, we profiled more than 200 CRISPR-mediated HAP1 cell knockout lines using mass spectrometry-based multiomics analyses. This effort generated approximately 8.3 million distinct biomolecule measurements, providing a deep survey of the cellular responses to mitochondrial perturbations and laying a foundation for mechanistic investigations into protein function. Guided by these data, we discovered that PIGY upstream open reading frame (PYURF) is an S-adenosylmethionine-dependent methyltransferase chaperone that supports both complex I assembly and coenzyme Q biosynthesis and is disrupted in a previously unresolved multisystemic mitochondrial disorder. We further linked the putative zinc transporter SLC30A9 to mitochondrial ribosomes and OxPhos integrity and established RAB5IF as the second gene harbouring pathogenic variants that cause cerebrofaciothoracic dysplasia. Our data, which can be explored through the interactive online MITOMICS.app resource, suggest biological roles for many other orphan mitochondrial proteins that still lack robust functional characterization and define a rich cell signature of mitochondrial dysfunction that can support the genetic diagnosis of mitochondrial diseases.

Date: 2022
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DOI: 10.1038/s41586-022-04765-3

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