Succinylation-dependent mitochondrial translocation of PKM2 promotes cell survival in response to nutritional stress

Cell Death & Disease
Hailong QiYuxin Yin

Abstract

Tumor growth and progression is characteristically associated with the synergistic effects of uncontrolled cellular proliferation and cell survival under stress. Pyruvate kinase M2 (PKM2) contributes to both of these effects. However, the specific mechanism by which PKM2 promotes uncontrolled proliferation or cell survival under stress in different nutritional environments is unclear. We show that succinylation mediated mitochondrial translocation of PKM2 under glucose starvation plays a role in switching the cellular machinery from proliferation to cell survival mode and vice versa. Mitochondrial PKM2 inhibits ubiquitination-mediated degradation of voltage-dependent anion channel 3 (VDAC3) and increases mitochondrial permeability to generate more ATP for cell survival under nutritional depletion. We found there is a positive correlation of upregulation of mitochondrial PKM2 and upregulation of VDAC3 in human colon cancer. This shows the mechanisms identified in this study in fact play a role in neoplastic biology. We therefore developed a small molecule designated compound 8 that blocks mitochondrial translocation of PKM2 and inhibits tumor development. Our data suggest that blocking PKM2 mitochondrial function with a small mo...Continue Reading

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Citations

Oct 28, 2019·Bioscience Reports·Ting TaoXiaoping Yang
Jul 30, 2020·International Journal of Molecular Sciences·Chih-Hao Wang, Yau-Huei Wei
Aug 30, 2020·Journal of Experimental & Clinical Cancer Research : CR·Xiang LiQiang You
Jan 15, 2021·Cancer Letters·Felipe ParedesAlejandra San Martin
Jan 29, 2021·International Journal of Molecular Sciences·Dexter L PuckettAhmed Bettaieb
May 11, 2021·Metabolomics : Official Journal of the Metabolomic Society·Gilson Costa Dos SantosNatália Mesquita de Brito
May 22, 2021·Ecotoxicology and Environmental Safety·Zhijuan HuangChaoliang Lei
Jun 9, 2021·Life Sciences·Abu Sufiyan Chhipa, Snehal Patel
Jul 9, 2021·Life Sciences·Shahab Shahgaldi, Fatemeh Rezaei Kahmini
Jul 27, 2021·Journal of Cellular Physiology·Yoon-Beom LeeJae-Bong Park

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Methods Mentioned

BETA
nuclear translocation
pull down
pull-down
ubiquitination
immunoprecipitation
Assay
xenograft
environmental stress
xenografts
chemical modification

Software Mentioned

GraphPad Prism

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