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

144 Citations (Scopus)

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

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Insulin Resistance
Insulin Receptor Substrate Proteins
Organelle Biogenesis
Wnt Proteins
Insulin
Mitochondrial Genes
Cell Aging
Mitochondrial Proteins
RNA Interference
DNA Damage
Reactive Oxygen Species
Mitochondria
Homeostasis
Glucose

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Yoon, J. C., Ng, A., Kim, B. H., Bianco, A., Xavier, R. J., & Elledge, S. J. (2010). Wnt signaling regulates mitochondrial physiology and insulin sensitivity. Genes and Development, 24(14), 1507-1518. https://doi.org/10.1101/gad.1924910

Wnt signaling regulates mitochondrial physiology and insulin sensitivity. / Yoon, John C.; Ng, Aylwin; Kim, Brian H.; Bianco, Antonio; Xavier, Ramnik J.; Elledge, Stephen J.

In: Genes and Development, Vol. 24, No. 14, 15.07.2010, p. 1507-1518.

Research output: Contribution to journalArticle

Yoon, JC, Ng, A, Kim, BH, Bianco, A, Xavier, RJ & Elledge, SJ 2010, 'Wnt signaling regulates mitochondrial physiology and insulin sensitivity', Genes and Development, vol. 24, no. 14, pp. 1507-1518. https://doi.org/10.1101/gad.1924910
Yoon JC, Ng A, Kim BH, Bianco A, Xavier RJ, Elledge SJ. Wnt signaling regulates mitochondrial physiology and insulin sensitivity. Genes and Development. 2010 Jul 15;24(14):1507-1518. https://doi.org/10.1101/gad.1924910
Yoon, John C. ; Ng, Aylwin ; Kim, Brian H. ; Bianco, Antonio ; Xavier, Ramnik J. ; Elledge, Stephen J. / Wnt signaling regulates mitochondrial physiology and insulin sensitivity. In: Genes and Development. 2010 ; Vol. 24, No. 14. pp. 1507-1518.
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