Journal Article

Systems proteomics of liver mitochondria function

Williams, Evan G., Jha, Pooja, Zamboni, Nicola, Wolski, Witold, Dubuis, Sébastien, Amariuta, Tiffany, Blattmann, Peter, Argmann, Carmen A., Houten, Sander M., Aebersold, Ruedi, Auwerx, Johan, Wu, Yibo

2016

Overview

Combined analysis of large data sets characterizing genes, transcripts, and proteins can elucidate biological functions and disease processes. Williams et al. report an exceptionally detailed characterization of mitochondrial function in a genetic reference panel of recombinant inbred mice. They measured the metabolic function of nearly 400 mice under various environmental conditions and collected detailed quantitative information from livers of the animals on over 25,000 transcripts. These data were integrated with quantitation of over 2500 proteins and nearly 1000 metabolites. Such analysis showed a frequent lack of correlation of transcript and protein abundance, enabled the identification of genomic variants of mitochondrial enzymes that caused inborn errors in metabolism, and revealed two genes that appear to function in cholesterol metabolism. Science , this issue p. 10.1126/science.aad0189 Advances in mass spectrometry yield insights into mitochondrial function. Recent improvements in quantitative proteomics approaches, including Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS), permit reproducible large-scale protein measurements across diverse cohorts. Together with genomics, transcriptomics, and other technologies, transomic data sets can be generated that permit detailed analyses across broad molecular interaction networks. Here, we examine mitochondrial links to liver metabolism through the genome, transcriptome, proteome, and metabolome of 386 individuals in the BXD mouse reference population. Several links were validated between genetic variants toward transcripts, proteins, metabolites, and phenotypes. Among these, sequence variants in Cox7a2l alter its protein’s activity, which in turn leads to downstream differences in mitochondrial supercomplex formation. This data set demonstrates that the proteome can now be quantified comprehensively, serving as a key complement to transcriptomics, genomics, and metabolomics—a combination moving us forward in complex trait analysis.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Amino acids / Analysis / Animals / Cardiovascular system / Cholesterol / Cholesterol - metabolism / Datasets / Diet / Electron Transport Complex IV - genetics / Electron Transport Complex IV - metabolism / Environmental conditions / Gene mapping / Genetic factors / Genetic variance / Genetic Variation / Genetics / Genomics / Heart rate / Hep G2 Cells / Humans / Links / Liver / Liver - metabolism / Mass spectra / Mass spectrometry / Meta Analysis / Metabolic Networks and Pathways - genetics / Metabolism / Metabolites / Metabolome / Metabolomics / Mice / Mice, Inbred Strains / Mitochondria / Mitochondria, Liver - genetics / Mitochondria, Liver - metabolism / Molecular Sequence Data / Proteins / Proteome / Proteomics / Quantitative Trait Loci / RESEARCH ARTICLE SUMMARY / Transcriptome / Transcripts (Written Records)