T cell activation is driven by an ADP-dependent glucokinase linking enhanced glycolysis with mitochondrial reactive oxygen species generation

Cell Rep. 2012 Nov 29;2(5):1300-15. doi: 10.1016/j.celrep.2012.10.009. Epub 2012 Nov 15.


Mitochondria-originating reactive oxygen species (ROS) control T cell receptor (TCR)-induced gene expression. Here, we show that TCR-triggered activation of ADP-dependent glucokinase (ADPGK), an alternative, glycolytic enzyme typical for Archaea, mediates generation of the oxidative signal. We also show that ADPGK is localized in the endoplasmic reticulum and suggest that its active site protrudes toward the cytosol. The ADPGK-driven increase in glycolytic metabolism coincides with TCR-induced glucose uptake, downregulation of mitochondrial respiration, and deviation of glycolysis toward mitochondrial glycerol-3-phosphate dehydrogenase(GPD) shuttle; i.e., a metabolic shift to aerobic glycolysis similar to the Warburg effect. The activation of respiratory-chain-associated GPD2 results in hyperreduction of ubiquinone and ROS release from mitochondria. In parallel, mitochondrial bioenergetics and ultrastructure are altered. Downregulation of ADPGK or GPD2 abundance inhibits oxidative signal generation and induction of NF-κB-dependent gene expression, whereas overexpression of ADPGK potentiates them.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Archaea / enzymology
  • Down-Regulation
  • Endoplasmic Reticulum / enzymology
  • Glucokinase / antagonists & inhibitors
  • Glucokinase / chemistry
  • Glucokinase / metabolism*
  • Glycerolphosphate Dehydrogenase / antagonists & inhibitors
  • Glycerolphosphate Dehydrogenase / genetics
  • Glycerolphosphate Dehydrogenase / metabolism
  • Glycolysis
  • Humans
  • Jurkat Cells
  • Lymphocyte Activation
  • Mitochondria / enzymology
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Molecular Sequence Data
  • NF-kappa B / metabolism
  • Protein Structure, Secondary
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Reactive Oxygen Species / metabolism*
  • Receptors, Antigen, T-Cell / metabolism
  • Sequence Alignment
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • Ubiquinone / metabolism


  • NF-kappa B
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Receptors, Antigen, T-Cell
  • Ubiquinone
  • Glycerolphosphate Dehydrogenase
  • ADP-dependent glucokinase
  • Glucokinase