MassIVE MSV000086685

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

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Description

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. [doi:10.25345/C5XN5B] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: discovery lipidomics ; Shotgun proteomics ; untargeted metabolomics ; multi-omics ; large-scale ; human cell line ; CRISPR knockout

Contact

Principal Investigators:
(in alphabetical order) 		Joshua J. Coon, University of Wisconsin-Madison, USA
Submitting User: shishkova

Publications

Rensvold JW, Shishkova E, Sverchkov Y, Miller IJ, Cetinkaya A, Pyle A, Manicki M, Brademan DR, Alanay Y, Raiman J, Jochem A, Hutchins PD, Peters SR, Linke V, Overmyer KA, Salome AZ, Hebert AS, Vincent CE, Kwiecien NW, Rush MJP, Westphall MS, Craven M, Akarsu NA, Taylor RW, Coon JJ, Pagliarini DJ.
Defining mitochondrial protein functions through deep multiomic profiling.
Nature. 2022 Jun;606(7913):382-388. Epub 2022 05 25.

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GNPS content goes here (MSV000086685 [task=9a79911bd36e4f02baf0ea1d108511e6])
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Number of distinct conditions across all analyses (original submission and reanalyses) associated with this dataset.

Distinct condition labels are counted across all files submitted in the "Metadata" category having a "Condition" column in this dataset.

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Number of distinct biological replicates across all analyses (original submission and reanalyses) associated with this dataset.

Distinct replicate labels are counted across all files submitted in the "Metadata" category having a "BioReplicate" or "Replicate" column in this dataset.

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Number of distinct technical replicates across all analyses (original submission and reanalyses) associated with this dataset.

The technical replicate count is defined as the maximum number of times any one distinct combination of condition and biological replicate was analyzed across all files submitted in the "Metadata" category. In the case of fractionated experiments, only the first fraction is considered.

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Originally identified proteins that were automatically remapped by MassIVE to proteins in the SwissProt human reference database.

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Number of distinct protein accessions reported across all analyses (original submission and reanalyses) associated with this dataset.

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Number of distinct unmodified peptide sequences reported across all analyses (original submission and reanalyses) associated with this dataset.

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Number of distinct peptide sequences (including modified variants or peptidoforms) reported across all analyses (original submission and reanalyses) associated with this dataset.

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Total number of peptide-spectrum matches (i.e. spectrum identifications) reported across all analyses (original submission and reanalyses) associated with this dataset.

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Number of distinct proteins quantified across all analyses (original submission and reanalyses) associated with this dataset.

Distinct protein accessions are counted across all files submitted in the "Statistical Analysis of Quantified Analytes" category having a "Protein" column in this dataset.

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Number of distinct proteins found to be differentially abundant in at least one comparison across all analyses (original submission and reanalyses) associated with this dataset.

A protein is differentially abundant if its change in abundance across conditions is found to be statistically significant with an adjusted p-value <= 0.05 and lists no issues associated with statistical tests for differential abundance.

Distinct protein accessions are counted across all files submitted in the "Statistical Analysis of Quantified Analytes" category having a "Protein" column in this dataset.

"N/A" means no results of this type were submitted.
This dataset may not contain all raw spectra data as originally deposited in PRIDE. It has been imported to MassIVE for reanalysis purposes, so its spectra data here may consist solely of processed peak lists suitable for reanalysis with most software.