Regulation of Pyruvate Dehydrogenase Complex in Cancer Metabolism

Cancer cells often reprogramme energy metabolism to support rapid proliferation and survival under stress. Central to this shift is the pyruvate dehydrogenase complex (PDC), a mitochondrial multi-enzyme assembly that catalyses the oxidative decarboxylation of pyruvate to acetyl-CoA, thereby linking glycolysis to the tricarboxylic acid cycle. In many tumours, PDC activity is suppressed by increased expression or activation of pyruvate dehydrogenase kinases (PDKs), which phosphorylate and inactivate the catalytic E1 subunit. This inhibition fosters glycolytic flux and lactate production even in aerobic conditions, a hallmark known as the Warburg effect. Conversely, phosphatases such as pyruvate dehydrogenase phosphatases (PDPs) can reactivate the complex, restoring mitochondrial respiration. Emerging research has unveiled layers of regulation beyond phosphorylation, including post-translational modifications, small-RNA-mediated control and metabolic feedback loops. Dysregulation of the PDC axis contributes not only to energy reallocation but also to biosynthetic and redox homeostasis, immune evasion and resistance to therapy. Understanding these regulatory networks holds promise for interventions that re-enable mitochondrial metabolism to inhibit tumour growth and improve treatment outcomes.

Research from Nature Portfolio

Recent studies have identified mitochondrial KMT9 as a novel regulator of the pyruvate dehydrogenase complex in prostate cancer. KMT9 translocates to the mitochondria and monomethylates the DLAT subunit on lysine 596, enhancing complex activity, de novo lipogenesis and tumour proliferation both in vitro and in vivo. Analyses of patient specimens reveal that mitochondrial KMT9 levels and DLAT K596 methylation positively correlate with disease severity. This discovery offers a therapeutic strategy to selectively impair cancer cell metabolism by targeting a histone methyltransferase with dual nuclear and mitochondrial functions.

Regulation of Pyruvate Dehydrogenase Complex in Cancer Metabolism publication trend

The graph below shows the total number of articles in regulation of pyruvate dehydrogenase complex in cancer metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

Pyruvate dehydrogenase complex (PDC): Multi-enzyme assembly that converts pyruvate into acetyl-CoA, linking glycolysis to the tricarboxylic acid cycle within mitochondria.

Pyruvate dehydrogenase kinase (PDK): Family of kinases that phosphorylate and inhibit the PDC, shifting cellular metabolism towards glycolysis.

Dihydrolipoamide transacetylase (DLAT): E2 subunit of the PDC responsible for transferring the acetyl group from pyruvate to coenzyme A.

Lysine methylation: Post-translational modification involving addition of methyl groups to lysine residues, modulating protein activity or interactions.

Hypoxia-inducible factor-1α (HIF-1α): Oxygen-sensitive transcription factor that induces genes for glycolysis and angiogenesis under low-oxygen conditions.

References

1. Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth. Nature Communications (2025).
2. PRMT3 drives PD-L1-mediated immune escape through activating PDHK1-regulated glycolysis in hepatocellular carcinoma. Cell Death & Disease (2025).
3. PDK1 promotes breast cancer progression by enhancing the stability and transcriptional activity of HIF-1α. Genes & Diseases (2023).
4. MiR-422a regulates cellular metabolism and malignancy by targeting pyruvate dehydrogenase kinase 2 in gastric cancer. Cell Death & Disease (2018).