Wnt signaling regulates mitochondrial physiology and insulin sensitivity.
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.
Yoon
John C
JC
Howard Hughes Medical Institute, Division of Genetics, Brigham and Women's Hospital, Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Ng
Aylwin
A
Kim
Brian H
BH
Bianco
Antonio
A
Xavier
Ramnik J
RJ
Elledge
Stephen J
SJ
D000818:Animals; D016922:Cellular Senescence; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*
D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; D051153:Wnt Proteins