Roles of GSK3 in metabolic shift toward abnormal anabolism in cell senescence

Annals of the New York Academy of Sciences
You-Mie KimGyesoon Yoon

Abstract

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.

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Citations

Aug 15, 2012·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Melissa D Lehti-Shiu, Shin-Han Shiu
Nov 13, 2015·Biochemical and Biophysical Research Communications·Xiaojing HuHongyan Tian
Dec 17, 2011·Journal of Hepatology·Lars P BechmannAli Canbay
Mar 8, 2014·Cell Cycle·Alexey A MoskalevAlex Zhavoronkov
Oct 30, 2014·International Journal of Molecular Medicine·Nana TokuhiraYasunori Ogura
Feb 7, 2015·Aging and Disease·Amanda Piano, Vladimir I Titorenko
Oct 25, 2016·Critical Reviews in Biochemistry and Molecular Biology·Julia Jellusova, Robert C Rickert
Mar 18, 2017·SLAS Technology·Ali Zarrinpar
Jan 31, 2018·Oxidative Medicine and Cellular Longevity·Romina MancinelliClaudia Giampietri
Sep 5, 2017·Journal of the American Geriatrics Society·James L KirklandPaul D Robbins
Mar 13, 2020·Nature Reviews. Endocrinology·Sundeep KhoslaJames L Kirkland
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Jun 17, 2014·Oncotarget·James A McCubreyMelchiorre Cervello
Feb 19, 2015·The Journal of Biological Chemistry·Seung-Won ChoiKyung-Hee Chun

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