Wnt signaling regulates mitochondrial physiology and insulin sensitivity

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.[Keywords: RNAi screen; mitochondria; Wnt signaling; IRS-1] Supplemental material is available at http://www.genesdev.org.

Wnt-5a Ligand Modulates Mitochondrial Fission-Fusion in Rat Hippocampal Neurons

“…Taken together, these findings support a model of adipogenesis in which sFRP inhibits Wnt signaling to suppress oxidative metabolism and stimulate adipocyte growth during obesity (23). Wnt signaling also regulates mitochondrial physiology and insulin sensitivity (20). Regulation of mitochondrial division is critical for normal cellular function.…”

“…Wnt signaling activates mitochondrial biogenesis, which in turn produces elevated levels of reactive oxidative species (ROS) and oxidative damage (20). This effect on mitochondrial function and ROS generation may likely be responsible for some of the major biological consequences of altered Wnt signaling (21).…”

Role of WNT pathway in the determination of human mesenchymal stem cells into preadipocytes

“…During the last several years, it has been shown that the development of brown fat tissue is also significantly inhibited by canonical WNT signalling (Kang et al 2005). However, it should also be mentioned that mitochondrial biogenesis itself was found to be increased in response to WNT molecules , Yoon et al 2010. In summary, these molecular, cellular and physiological findings clearly demonstrate a crucial role for WNT signalling in rodent and human white and brown adipogenesis.…”

Osteochondrosis-Related Gene Expression in Equine Leukocytes Differs among Affected Joints in Foals

“…Recently, abnormal mitochondria and endoplasmic reticulum were observed in the deep zone of OC cartilage [29]. The mitochondrial dysfunction could be partially explained by the altered Wnt signaling pathway observed in the OC-affected horses because this pathway is known as a key regulator of mitochondrial function [17,30]. Furthermore, Power et al [31] demonstrated by immunohistochemistry that sclerostin, a major inhibitor peptide of the canonical Wnt pathway signaling was increased in naturally occurring lesions of equine osteochondrosis.…”

“…The aim of this study is to compare in young OC-affected horses (between 8 to 12 months), the different expression of selected genes depending the joints involved. 30 Belgian Warmblood horses with osteochondrosis and 11 Belgian Warmblood horses free of osteochondrosis were included in this study. All horses were between 8 to 12 months old.…”