Succinylation-dependent Mitochondrial Translocation of PKM2 Promotes Cell Survival in Response to Nutritional Stress

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2019 Feb 22

PMID 30787272

Citations 44

Authors

Hailong Qi

Xianling Ning

Chang Yu

Xin Ji

Yan Jin

Michael A McNutt

Yuxin Yin

Affiliations

Soon will be listed here.

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 molecule inhibitor has potential for cancer treatment.

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