Dataset Information

MITOMICS: defining mitochondrial protein functions through deep multi-omic profiling

ABSTRACT: Mitochondria are epicenters of eukaryotic metabolism and bioenergetics. Pioneering efforts in recent decades have established the core protein componentry of these organelles and have linked their dysfunction to over 150 distinct disorders. However, hundreds of mitochondrial proteins still lack clear functions, and ~40% of mitochondrial disorders remain unresolved. To establish a more complete functional compendium of human mitochondrial proteins, we profiled 203 CRISPR-mediated HAP1 cell knockout lines using mass spectrometry-based multi-omics analyses. This effort generated ~8.2 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 PYURF is a SAM-dependent methyltransferase chaperone that supports both complex I assembly and coenzyme Q biosynthesis, and that is disrupted in a previously unresolved multisystemic mitochondrial disorder. We further linked the putative zinc transporter SLC30A9 to mitoribosome and OxPhos integrity and established RAB5IF as the second gene harboring pathogenic variants causing cerebrofaciothoracic dysplasia. Our data - which can be explored through an interactive online resource - suggest biological roles for many other orphan mitochondrial proteins still lacking robust functional characterization, and define a rich cell signature of mitochondrial dysfunction that can support the genetic diagnosis of mitochondrial diseases.

INSTRUMENT(S): Q Exactive GC-MS Orbitrap (Thermo Scientific), Orbitrap Fusion Lumos, Q Exactive HF

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Joshua J. Coon

PROVIDER: MSV000086685 | MassIVE | Mon Jan 11 16:18:00 GMT 2021

REPOSITORIES: MassIVE

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Defining mitochondrial protein functions through deep multiomic profiling.

Rensvold Jarred W JW Shishkova Evgenia E Sverchkov Yuriy Y Miller Ian J IJ Cetinkaya Arda A Pyle Angela A Manicki Mateusz M Brademan Dain R DR Alanay Yasemin Y Raiman Julian J Jochem Adam A Hutchins Paul D PD Peters Sean R SR Linke Vanessa V Overmyer Katherine A KA Salome Austin Z AZ Hebert Alexander S AS Vincent Catherine E CE Kwiecien Nicholas W NW Rush Matthew J P MJP Westphall Michael S MS Craven Mark M Akarsu Nurten A NA Taylor Robert W RW Coon Joshua J JJ Pagliarini David J DJ

Nature 20220525 7913

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 fun ...[more]

PMID: 35614220

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