Wnt signaling regulates mitochondrial physiology and insulin sensitivity
- John C. Yoon1,2,
- Aylwin Ng3,
- Brian H. Kim4,
- Antonio Bianco4,
- Ramnik J. Xavier3 and
- Stephen J. Elledge1,5
- 1Howard Hughes Medical Institute, Division of Genetics, Brigham and Women's Hospital, Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 2Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA;
- 3Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA;
- 4Thyroid Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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.
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Footnotes
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↵5 Corresponding author.
E-MAIL selledge{at}genetics.med.harvard.edu; FAX (617) 525-4500
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1924910.
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Supplemental material is available at http://www.genesdev.org.
- Received March 11, 2010.
- Accepted June 7, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press