Roles of GSK3 in metabolic shift toward abnormal anabolism in cell senescence.
Diverse metabolic alterations, including mitochondrial dysfunction, have often been reported as characteristic phenotypes of senescent cells. However, the overall consequence of senescent metabolic features, how they develop, and how they are linked to other senescent phenotypes, such as enlarged cell volume, increased granularity, and oxidative stress, is not clear. We investigated the potential roles of glycogen synthase kinase 3 (GSK3), a multifunctional kinase, in the development of the metabolic phenotypes in cell senescence. The inactivation of GSK3 via phosphorylation is commonly observed in diverse cell senescences. Furthermore, subcytotoxic concentration of GSK3 inhibitor was sufficient to induce cellular senescence, accompanied by augmented anabolism, such as enhanced protein synthesis, and increased glycogenesis and lipogenesis, in addition to mitochondrial dysfunction. Anabolism was accomplished through glycogen synthase, eIF2B, and SREBP1. These metabolic features seem to contribute to an increase in cellular mass by increasing glycogen granules, protein mass, and organelles. Taken together, our results suggest that GSK3 is one of the key modulators of metabolic alteration, leading the cells to senescence.
Kim
You-Mie
YM
Department of Biochemistry and Molecular Biology, The Graduate School, Ajou University, Suwon, Korea.
Seo
Yong-Hak
YH
Park
Chan-Bae
CB
Yoon
Soo-Han
SH
Yoon
Gyesoon
G
D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D005456:Fluorescent Dyes / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D018384:Oxidative Stress; D010101:Oxygen Consumption; D010641:Phenotype; D010766:Phosphorylation; D017382:Reactive Oxygen Species; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism
D005456:Fluorescent Dyes; D017382:Reactive Oxygen Species; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D038362:Glycogen Synthase Kinase 3