Jonathan A Stefely1,2,6, Nicholas W Kwiecien3,4,6, Elyse C Freiberger3,5, Alicia L Richards3,4, Adam Jochem1, Matthew J P Rush3,4, Arne Ulbrich3,4, Kyle P Robinson1,2, Paul D Hutchins3,4, Mike T Veling1,2, Xiao Guo1,4, Zachary A Kemmerer1,2, Kyle J Connors3,4, Edna A Trujillo3,4, Jacob Sokol1,2, Harald Marx3, Michael S Westphall3, Alexander S Hebert3, David J Pagliarini1,2,7 & Joshua J Coon3–5,7
Nat Biotechnol. 2016 Nov;34(11):1191-1197
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 molecular insights into mitochondrial protein functions.
1. orgridge Institute for Research, Madison, Wisconsin, USA. 2. Department of Biochemistry, University of Wisconsinâ€“Madison, Madison, Wisconsin, USA. 3. Genome Center of Wisconsin, Madison, Wisconsin, USA. 4. Department of Chemistry, University of Wisconsin–Madison, Madison, Wisconsin, USA. 5. Department of Biomolecular Chemistry, University of Wisconsin–Madison, Madison, Wisconsin, USA. 6. These authors contributed equally to this work. 7. These authors jointly supervised this work.