Overexpression of PKM2 promotes mitochondrial fusion through attenuated p53 stability

Abstract

M2-type pyruvate kinase (PKM2) contributes to the Warburg effect. However, it remains unknown as to whether PKM2 has an inhibitory effect on mitochondrial function. We report in this work that PKM2 overexpression inhibits the expression of Drp1 and results in the mitochondrial fusion. The ATP production was found to be decreased, the mtDNA copy number elevated and the expression level of electron transport chain (ETC) complex I, III, V depressed in PKM2 overexpressed cells. PKM2 overexpression showed a decreased p53 protein level and a shorter p53 half-life. In contrast, PKM2 knockdown resulted in increased p53 expression and prolonged half-life of p53. PKM2 could directly bind with both p53 and MDM2 and promote MDM2-mediated p53 ubiquitination. The dimeric PKM2 significantly suppressed p53 expression compared with the other PKM2 mutants. The reverse relationship between PKM2 and Drp1 was further confirmed in a large number of clinical samples. Taken together, the present results highlight a new mechanism that link PKM2 to mitochondrial function, based on p53-Drp1 axis down regulation, revealing a novel therapeutic target in patients with abnormal mitochondria.

Biventricular Increases in Mitochondrial Fission Mediator (MiD51) and Proglycolytic Pyruvate Kinase (PKM2) Isoform in Experimental Group 2 Pulmonary Hypertension-Novel Mitochondrial Abnormalities

“…Recently, Liang et al report that PKM2 translocates to mitochondria under oxidative stress (30). Furthermore, Wu et al show that PKM2 overexpression inhibits the expression of Drp1 and induces mitochondrial fusion in HeLa and HCT-116 cells (31). However, we observe that mitochondria within the cardiomyocytes of both ventricles are fragmented and depolarized (Figures 4, 5).…”

PKM2: A Potential Regulator of Rheumatoid Arthritis via Glycolytic and Non-Glycolytic Pathways

“…In MCF7 cells exposed to DNA-damaging agent, PKM2 inhibited transactivation of the p21 gene by preventing p53 binding to the p21 promoter, leading to a nonstop G1 phase (58). Dimeric PKM2 has been found to bind directly with both p53 and MDM2 and to promote MDM2-mediated p53 ubiquitination (59). PKM2 gene silencing suppresses proliferation and promotes apoptosis in LS-147T and SW620 cells, accompanied by increased p53 and p21 expression (60).…”

Pyruvate Kinase M2 and Cancer: The Role of PKM2 in Promoting Tumorigenesis

“…Tumor cells are different from healthy cells in the sense that they are dependent on aerobic glycolysis to produce energy even if there is sufficient oxygen in the surroundings (1)(2)(3). This switching of the cell from the normal respiratory pathway to aerobic glycolysis is known as the Warburg effect (1)(2)(3). The cancer cell produces additional energy by increasing the reaction rate of glycolysis with the production of lactate in cytosol (4).…”