Wnt signaling regulates mitochondrial physiology and insulin sensitivity

John C. Yoon, Aylwin Ng, Brian H. Kim, Antonio Bianco, Ramnik J. Xavier, Stephen J. Elledge

Research output: Contribution to journalArticle

153 Scopus citations

Abstract

Mitochondria serve a critical role in physiology and disease. The genetic basis of mitochondrial regulation in mammalian cells has not yet been detailed. We performed a large-scale RNAi screen to systematically identify genes that affect mitochondrial abundance and function. This screen revealed previously unrecognized roles for >150 proteins in mitochondrial regulation. We report that increased Wnt signals are a potent activator of mitochondrial biogenesis and reactive oxygen species (ROS) generation, leading to DNA damage and acceleration of cellular senescence in primary cells. The signaling protein insulin receptor substrate-1 (IRS-1), shown here to be a transcriptional target of Wnt, is induced in this setting. The increased level of IRS-1 drives activation of mitochondrial biogenesis; furthermore, in insulin-responsive cell types, it enhances insulin signaling, raising the possibility that Wnt proteins may be used to modulate glucose homeostasis. Our results identify a key component of the mitochondrial regulatory apparatus with a potentially important link to metabolic and degenerative disorders.

Original languageEnglish (US)
Pages (from-to)1507-1518
Number of pages12
JournalGenes and Development
Volume24
Issue number14
DOIs
StatePublished - Jul 15 2010

Keywords

  • IRS-1
  • Mitochondria
  • RNAi screen
  • Wnt signaling

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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