Author
Listed:
- Jarred W. Rensvold
(Washington University School of Medicine
Morgridge Institute for Research)
- Evgenia Shishkova
(National Center for Quantitative Biology of Complex Systems
University of Wisconsin–Madison)
- Yuriy Sverchkov
(University of Wisconsin–Madison)
- Ian J. Miller
(National Center for Quantitative Biology of Complex Systems
University of Wisconsin–Madison)
- Arda Cetinkaya
(Hacettepe University)
- Angela Pyle
(Newcastle University
Newcastle University)
- Mateusz Manicki
(Washington University School of Medicine
Morgridge Institute for Research)
- Dain R. Brademan
(Morgridge Institute for Research
University of Wisconsin–Madison
University of Wisconsin–Madison)
- Yasemin Alanay
(Hacettepe University
Acibadem Mehmet Ali Aydinlar 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
National Center for Quantitative Biology of Complex Systems
University of Wisconsin–Madison)
- Austin Z. Salome
(University of Wisconsin–Madison)
- Alexander S. Hebert
(National Center for Quantitative Biology of Complex Systems
University of Wisconsin–Madison)
- Catherine E. Vincent
(University of Wisconsin–Madison)
- Nicholas W. Kwiecien
(National Center for Quantitative Biology of Complex Systems
University of Wisconsin–Madison)
- Matthew J. P. Rush
(University of Wisconsin–Madison)
- Michael S. Westphall
(National Center for Quantitative Biology of Complex Systems
University of Wisconsin–Madison)
- Mark Craven
(University of Wisconsin–Madison)
- Nurten A. Akarsu
(Hacettepe University)
- Robert W. Taylor
(Newcastle University
Newcastle University
Newcastle upon Tyne Hospitals NHS Foundation Trust)
- Joshua J. Coon
(Morgridge Institute for Research
National Center for Quantitative Biology of Complex Systems
University of Wisconsin–Madison
University of Wisconsin–Madison)
- David J. Pagliarini
(Washington University School of Medicine
Morgridge Institute for Research
National Center for Quantitative Biology of Complex Systems
Washington University School of Medicine)
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.
Suggested Citation
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. Hu, 2022.
"Defining mitochondrial protein functions through deep multiomic profiling,"
Nature, Nature, vol. 606(7913), pages 382-388, June.
Handle:
RePEc:nat:nature:v:606:y:2022:i:7913:d:10.1038_s41586-022-04765-3
DOI: 10.1038/s41586-022-04765-3
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