Yoon, John C.Ng, AylwinKim, Brian H.Bianco, AntonioXavier, Ramnik J.Elledge, Stephen J.2019-10-122010Yoon, J. C., A. Ng, B. H. Kim, A. Bianco, R. J. Xavier, and S. J. Elledge. 2010. “Wnt Signaling Regulates Mitochondrial Physiology and Insulin Sensitivity.” Genes & Development 24 (14): 1507–18. https://doi.org/10.1101/gad.1924910.0890-93691549-5477http://nrs.harvard.edu/urn-3:HUL.InstRepos:41542678Mitochondria 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.en-USJournal Article2019-10-1210.1101/gad.1924910