Abstract
Cancer cells preferentially metabolize glucose through aerobic glycolysis. This phenomenon, known as the Warburg effect, is a characteristic of glucose metabolism in cancer cells. PKM2 is reported to imply an important role in glycolysis. However, whether and how PKM2 can cause mitochondrial dysfunction, then subsequently forcing cancer cells using glycolysis instead of oxidation phosphorylation is poorly understood. Here we reported that overexpression of PKM2 disrupted mitochondrial dynamics by enhancing fusion. And PKM2 overexpression increased the expression of fusion protein Mfn2. Simultaneously, PKM2 overexpression induced mitochondrial dysfunctions shown by the decreased ATP level and increased mitochondrial DNA (mtDNA) copy number. Reduction of Mfn2 expression by siRNA attenuated the PKM2-enhanced mitochondrial fusion and restored the functions. Quantitative and morphological analyses showed that the expression of microRNA-106b (miR-106b) was decreased in the PKM2 overexpressed cells, and the reduction of Mfn2 expression and the recovery of mitochondrial functions were induced by the treatment of miR-106b mimics, demonstrating that miR-106b played important roles in the down-regulation of Mfn2 expression and the PKM2 mediation of mitochondrial fusion. Clinical investigation was performed and results showed that the higher expression levels of PKM2 corresponded with the higher expression levels of Mfn2 in breast cancer tissues by comparison of their expression in adjacent normal tissues. Taken together, our data demonstrate that the overexpression of PKM2 and Mfn2 causes mitochondrial dysfunction via enhancing mitochondrial fusion and miR-106b play crucial roles in PKM2 mediated mitochondrial function through its regulation of Mfn2 expression, which provides new insights into the molecular mechanisms underlying glycolysis and oxidative phosphorylation.