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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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Project description:Although mitochondrial dysfunctions are implicated in the pathogenesis of obesity, the molecular mechanisms underlying obesity-related metabolic abnormalities are still not well established. To acquire a comprehensive picture of mitochondrial molecular changes within metabolically active tissues, we focused on hepatic and muscle whole cellular transcriptome and mitochondrial proteome alterations in 16 and 48 weeks old high fat diet (HFD)-feed wild type C57BL/6J and hyperphagic, genetically modified mice with leptin dysfunction (ob/ob and db/db). On transcriptome level, the most discriminative hepatic alterations distinguished between genetically modified and wild type mice, and between overnight fasted and non-fasted mice, while the muscle transcriptional alterations related mainly to the fasting state. The fractions of uniquely different proteins were consistently higher in hyperphagic than in HFD-fed mice and in fasted than non-fasted mice . The liver samples revealed overall higher number of differentially expressed RNAs and proteins than muscle samples. Differentially expressed genes and proteins in the liver, but not in the muscle, could be assigned to several Gene Ontology terms, including oxidation-reduction and several metabolic processes. Thus, altered expression of genes and proteins accompanied the state of obesity and was quantitatively different in the liver and muscle. Our parallel microarray- and quantitative mitochondrial mass spectrometry-based study performed on hepatic and muscle samples identified a higher number of differentially expressed proteins than any other studies investigating obesity-related proteomes. However, even with our integrated transcriptomic and proteomic approach still many details and dynamics of a chain of metabolic events leading to obesity-related mitochondrial dysfunctions remain unresolved . 48 samples each of liver and muscle (total samples: 96). Samples splitted equally according to 3 criterions: age (24 young/24 old), fasting status (24 fasted/24 non fasted), and strain+diet (12 each: B6.V-Lep ob/J+D12450B, B6.BKS(D)-Lep rdb/J+D12450B, C57BL/6J+D12450B, C57BL/6J+D12492). Overall 3 replicates for each strain+diet/age/fasting_status combination. Low fat diet = D12450B; high fat diet = D12492.

Project description:This model is from the article: A metabolic model of the mitochondrion and its use in modelling diseases of the tricarboxylic acid cycle. Smith AC, Robinson AJ. BMC Syst Biol. 2011 Jun 29;5(1):102. 21714867 , Abstract: BACKGROUND:Mitochondria are a vital component of eukaryotic cells and their dysfunction is implicated in a large number of metabolic, degenerative and age-related human diseases. The mechanism or these disorders can be difficult to elucidate due to the inherent complexity of mitochondrial metabolism. To understand how mitochondrial metabolic dysfunction contributes to these diseases, a metabolic model of a human heart mitochondrion was created. RESULTS: A new model of mitochondrial metabolism was built on the principle of metabolite availability using MitoMiner, a mitochondrial proteomics database, to evaluate the subcellular localisation of reactions that have evidence for mitochondrial localisation. Extensive curation and manual refinement was used to create a model called iAS253, containing 253 reactions, 245 metabolites and 89 transport steps across the inner mitochondrial membrane. To demonstrate the predictive abilities of the model, flux balance analysis was used to calculate metabolite fluxes under normal conditions and to simulate three metabolic disorders that affect the TCA cycle: fumarase deficiency, succinate dehydrogenase deficiency and alpha-ketoglutarate dehydrogenase deficiency. CONCLUSION: The results of simulations using the new model corresponded closely with phenotypic data under normal conditions and provided insight into the complicated and unintuitive phenotypes of the three disorders, including the effect of interventions that may be of therapeutic benefit, such as low glucose diets or amino acid supplements. The model offers the ability to investigate other mitochondrial disorders and can provide the framework for the integration of experimental data in future studies. Created by Anthony C. Smith (Mon Mar 14 11:03:11 2011) MRC - Mitochondrial Biology Unit, Cambridge, UK. acs@mrc-mbu.cam.ac.uk This metabolic network is a stocihiometric model of a human heart mitochondrion. Identifiers are KEGG Ids. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Dataset Information

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

Publications

Defining mitochondrial protein functions through deep multiomic profiling.

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