PDK (Pyruvate Dehydrogenase Kinase) [Neurosurgery Wiki]

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====== 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.

===== General Information =====
  * **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)

===== Role in Metabolism =====
  * 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

===== PDK in Glioblastoma and the Brain =====
  * 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**

===== Clinical Relevance =====
  * **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

===== PDK in TREM1-SYK Signaling (GBM Microglia) =====
  - TREM1 →
  - DAP12 →
  - SYK →
  - **PDK1** →
  - STAT3 →
  - Expression of pro-inflammatory and tumor-supportive genes in microglia