Multilayered genetic and omics dissection of mitochondrial activity in a mouse reference population.

Yibo Wu, Evan G. Williams, Sébastien Dubuis, Adrienne Mottis, Virginija Jovaisaite, Sander M. Houten, Carmen A. Argmann, Pouya Faridi, Witold Wolski, Zoltán Kutalik, Nicola Zamboni, Johan Auwerx, Ruedi Aebersold

Research output: Contribution to journalArticlepeer-review

183 Scopus citations

Abstract

The manner by which genotype and environment affect complex phenotypes is one of the fundamental questions in biology. In this study, we quantified the transcriptome--a subset of the metabolome--and, using targeted proteomics, quantified a subset of the liver proteome from 40 strains of the BXD mouse genetic reference population on two diverse diets. We discovered dozens of transcript, protein, and metabolite QTLs, several of which linked to metabolic phenotypes. Most prominently, Dhtkd1 was identified as a primary regulator of 2-aminoadipate, explaining variance in fasted glucose and diabetes status in both mice and humans. These integrated molecular profiles also allowed further characterization of complex pathways, particularly the mitochondrial unfolded protein response (UPR(mt)). UPR(mt) shows strikingly variant responses at the transcript and protein level that are remarkably conserved among C. elegans, mice, and humans. Overall, these examples demonstrate the value of an integrated multilayered omics approach to characterize complex metabolic phenotypes.

Original languageEnglish
Pages (from-to)1415-1430
Number of pages16
JournalCell
Volume158
Issue number6
DOIs
StatePublished - 2014
Externally publishedYes

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