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Title: Mitochondrial protein functions elucidated by multi-omic mass spectrometry profiling

Abstract

Mitochondrial dysfunction is associated with many human diseases, including cancer and neurodegeneration, that are often linked to proteins and pathways that are not well-characterized. To begin defining the functions of such poorly characterized proteins, we used mass spectrometry to map the proteomes, lipidomes and metabolomes of 174 yeast strains, each lacking a single gene related to mitochondrial biology. 144 of these genes have human homologs, 60 of which are associated with disease and 39 of which are uncharacterized. We present a multi-omic data analysis and visualization tool that we use to find covariance networks that can predict molecular functions, correlations between profiles of related gene deletions, gene-specific perturbations that reflect protein functions, and a global respiration deficiency response. Using this multi-omic approach, we link seven proteins including Hfd1p and its human homolog ALDH3A1 to mitochondrial coenzyme Q (CoQ) biosynthesis, an essential pathway disrupted in many human diseases. This Resource should provide broad molecular insights into mitochondrial protein functions.

Authors:
 [1];  [2];  [2];  [2];  [3];  [2];  [2];  [1];  [2];  [1];  [1];  [1];  [2];  [2];  [1];  [4];  [4];  [4];  [1];  [2]
  1. Univ. of Wisconsin, Madison, WI (United States); Morgridge Inst. for Research, Madison, WI (United States)
  2. Univ. of Wisconsin, Madison, WI (United States); Genome Center of Wisconsin, Madison, WI (United States)
  3. Morgridge Inst. for Research, Madison, WI (United States)
  4. Genome Center of Wisconsin, Madison, WI (United States)
Publication Date:
Research Org.:
Univ. of Wisconsin, Madison, WI (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1463133
Grant/Contract Number:  
FC02-07ER64494
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature Biotechnology
Additional Journal Information:
Journal Volume: 34; Journal Issue: 11; Journal ID: ISSN 1087-0156
Publisher:
Springer Nature
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Stefely, Jonathan A., Kwiecien, Nicholas W., Freiberger, Elyse C., Richards, Alicia L., Jochem, Adam, Rush, Matthew J. P., Ulbrich, Arne, Robinson, Kyle P., Hutchins, Paul D., Veling, Mike T., Guo, Xiao, Kemmerer, Zachary A., Connors, Kyle J., Trujillo, Edna A., Sokol, Jacob, Marx, Harald, Westphall, Michael S., Hebert, Alexander S., Pagliarini, David J., and Coon, Joshua J. Mitochondrial protein functions elucidated by multi-omic mass spectrometry profiling. United States: N. p., 2016. Web. doi:10.1038/nbt.3683.
Stefely, Jonathan A., Kwiecien, Nicholas W., Freiberger, Elyse C., Richards, Alicia L., Jochem, Adam, Rush, Matthew J. P., Ulbrich, Arne, Robinson, Kyle P., Hutchins, Paul D., Veling, Mike T., Guo, Xiao, Kemmerer, Zachary A., Connors, Kyle J., Trujillo, Edna A., Sokol, Jacob, Marx, Harald, Westphall, Michael S., Hebert, Alexander S., Pagliarini, David J., & Coon, Joshua J. Mitochondrial protein functions elucidated by multi-omic mass spectrometry profiling. United States. doi:10.1038/nbt.3683.
Stefely, Jonathan A., Kwiecien, Nicholas W., Freiberger, Elyse C., Richards, Alicia L., Jochem, Adam, Rush, Matthew J. P., Ulbrich, Arne, Robinson, Kyle P., Hutchins, Paul D., Veling, Mike T., Guo, Xiao, Kemmerer, Zachary A., Connors, Kyle J., Trujillo, Edna A., Sokol, Jacob, Marx, Harald, Westphall, Michael S., Hebert, Alexander S., Pagliarini, David J., and Coon, Joshua J. Mon . "Mitochondrial protein functions elucidated by multi-omic mass spectrometry profiling". United States. doi:10.1038/nbt.3683. https://www.osti.gov/servlets/purl/1463133.
@article{osti_1463133,
title = {Mitochondrial protein functions elucidated by multi-omic mass spectrometry profiling},
author = {Stefely, Jonathan A. and Kwiecien, Nicholas W. and Freiberger, Elyse C. and Richards, Alicia L. and Jochem, Adam and Rush, Matthew J. P. and Ulbrich, Arne and Robinson, Kyle P. and Hutchins, Paul D. and Veling, Mike T. and Guo, Xiao and Kemmerer, Zachary A. and Connors, Kyle J. and Trujillo, Edna A. and Sokol, Jacob and Marx, Harald and Westphall, Michael S. and Hebert, Alexander S. and Pagliarini, David J. and Coon, Joshua J.},
abstractNote = {Mitochondrial dysfunction is associated with many human diseases, including cancer and neurodegeneration, that are often linked to proteins and pathways that are not well-characterized. To begin defining the functions of such poorly characterized proteins, we used mass spectrometry to map the proteomes, lipidomes and metabolomes of 174 yeast strains, each lacking a single gene related to mitochondrial biology. 144 of these genes have human homologs, 60 of which are associated with disease and 39 of which are uncharacterized. We present a multi-omic data analysis and visualization tool that we use to find covariance networks that can predict molecular functions, correlations between profiles of related gene deletions, gene-specific perturbations that reflect protein functions, and a global respiration deficiency response. Using this multi-omic approach, we link seven proteins including Hfd1p and its human homolog ALDH3A1 to mitochondrial coenzyme Q (CoQ) biosynthesis, an essential pathway disrupted in many human diseases. This Resource should provide broad molecular insights into mitochondrial protein functions.},
doi = {10.1038/nbt.3683},
journal = {Nature Biotechnology},
number = 11,
volume = 34,
place = {United States},
year = {Mon Sep 26 00:00:00 EDT 2016},
month = {Mon Sep 26 00:00:00 EDT 2016}
}

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Cited by: 18 works
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Works referenced in this record:

Clustal W and Clustal X version 2.0
journal, September 2007


MUSCLE: multiple sequence alignment with high accuracy and high throughput
journal, March 2004

  • Edgar, R. C.
  • Nucleic Acids Research, Vol. 32, Issue 5, p. 1792-1797
  • DOI: 10.1093/nar/gkh340