PDK (Pyruvate Dehydrogenase Kinase)

PDK is a mitochondrial kinase that regulates cellular energy metabolism by inhibiting the pyruvate dehydrogenase complex (PDC), thus controlling the flow of pyruvate into the tricarboxylic acid (TCA) cycle.

• Full name: Pyruvate Dehydrogenase Kinase
• Location: Mitochondrial matrix
• Function: Phosphorylates and inhibits the pyruvate dehydrogenase complex (PDC), preventing conversion of pyruvate to acetyl-CoA.
• Isoforms: PDK1, PDK2, PDK3, PDK4 (tissue-specific roles)

• Regulates the switch between:
  • Oxidative metabolism (via PDC and the TCA cycle)
  • Anaerobic glycolysis (producing lactate)
• Active PDK inhibits PDC → ↓ acetyl-CoA → ↓ TCA cycle activity
• Important in hypoxia, fasting, high-fat diets, and cancer metabolism

• In glioblastoma (GBM), PDK supports:
  • Aerobic glycolysis (Warburg effect)
  • Immune evasion
  • Rapid tumor growth
• PDK1 is activated downstream of SYK in microglia, contributing to:
  • STAT3 activation
  • Pro-tumor microglial plasticity
  • Immune suppression within the tumor microenvironment

• Diseases:
  • Cancer (especially GBM)
  • Diabetes and insulin resistance
  • Mitochondrial diseases
  • Neurodegenerative disorders
• Inhibitors:
  • Dichloroacetate (DCA):
    • Restores oxidative metabolism
    • Investigated in cancer and metabolic diseases
  • Newer selective inhibitors under development for PDK1 and PDK3

1. TREM1 →
2. DAP12 →
3. SYK →
4. PDK1 →
5. STAT3 →
6. Expression of pro-inflammatory and tumor-supportive genes in microglia