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

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.

Long noncoding RNA HULC accelerates the growth of human liver cancer stem cells by upregulating CyclinD1 through miR675-PKM2 pathway via autophagy

“…Interestingly, TLR2 enhances autophagy [46]. Importantly, PKM2 promotes cell survival [47] and regulates STAT3 [48]. In addition, miR-625-5p/PKM2 regulates glycolysis state [49].…”

Roles of Mitochondrial Sirtuins in Mitochondrial Function, Redox Homeostasis, Insulin Resistance and Type 2 Diabetes

“…Pyruvate kinase muscle isozyme 2 (PKM2), which catalyzes the last step of glycolysis to dephosphorylate phosphoenolpyruvate to pyruvate, has been identified as a target of SIRT5 [82,83]. It has been shown that succinylation of PKM2 increases its enzymatic activity.…”

“…Inhibition of SIRT5 or substitution of succinylated mimetic mutation (K498E) on PKM2 could increase cell death in response to oxidative stress [82]. In contrast, another group observed that SIRT5-mediated desuccinylation of PMK2 impairs its translocation to mitochondria and stabilization of voltage-dependent anion channel 3 (VDAC3), which led to the opening of mPTP and apoptosis under glucose deprivation [83]. The discrepancy from the above two studies may be resulted from different stress conditions (oxidative stress vs. nutrient stress), cell types (lung cancer cells vs. colon cancer cells) or localization of PKM2 (cytosol vs. mitochondria).…”

The molecular mechanisms of LncRNA-correlated PKM2 in cancer metabolism

“…In addition to phosphorylation and O’GlcNAcylation, which regulates the activity of PKM2, PKM2 can also be modified by other post-translational modifications, including acetylation [28], succinylation [29] and methylation [30]. For instance, under normal glucose conditions, deacetylated hnRNP A1 reduced PKM2 in HCC cells and increased PKM1 alternative splicing, resulting in decreased metabolic activity of PK [31].…”