Regulation of pyruvate dehydrogenase complex: Dancing to different drums in cancer

Mechanisms governing the regulation of pyruvate dehydrogenase complex (PDC) are markedly modified in cancer cells compared to normal cells. PDC activity in normal cells is controlled by the reversible phosphorylation of three serine residues by dedicated kinases and phosphatases. Recent advances in metabolic reprogramming of glucose in cancer cells show that new and expanded mechanisms operate to regulate PDC. This comprehensive review presents several post-translational modifications of PDC proteins such as phosphorylation, acetylation, lactylation, methylation, and others (at least 12). Transcriptional regulation of PDC-specific kinase and phosphatase genes amplifies cancer-specific regulation of PDC. In some cancer cells, to enhance the mitochondrial oxidative metabolism to meet increased energy requirements, PDC is maintained in its active state by employing yet another novel mechanism involving AMPK-mediated phosphorylation of two different serine residues. Interestingly, impairment in PDC function as a major supplier of mitochondrial acetyl-CoA to the nuclear pool of acetyl-CoA is circumvented by the translocation of the PDC to the nucleus for histone acetylation. These cancer-specific PDC regulatory mechanisms represent an incredible advancement in our understanding of the reprogramming of cellular metabolism in cancer cells and could contribute to the development of new therapeutic strategies.