RIP3 Targets Pyruvate Dehydrogenase Complex to Increase Aerobic Respiration in TNF-induced Necroptosis

Nat Cell Biol. 2018 Feb;20(2):186-197. doi: 10.1038/s41556-017-0022-y. Epub 2018 Jan 22.

Abstract

Receptor-interacting protein kinase 3 (RIP3)-regulated production of reactive oxygen species (ROS) positively feeds back on tumour necrosis factor (TNF)-induced necroptosis, a type of programmed necrosis. Glutamine catabolism is known to contribute to RIP3-mediated ROS induction, but the major contributor is unknown. Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135. Upon activation, PDC enhances aerobic respiration and subsequent mitochondrial ROS production. Unexpectedly, mixed-lineage kinase domain-like (MLKL) is also required for the induction of aerobic respiration, and we further show that it is required for RIP3 translocation to meet mitochondria-localized PDC. Our data uncover a regulation mechanism of PDC activity, show that PDC activation by RIP3 is most likely the major mechanism activated by TNF to increase aerobic respiration and its by-product ROS, and suggest that RIP3-dependent induction of aerobic respiration contributes to pathologies related to oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics
  • Cell Death / genetics
  • Cell Respiration / genetics
  • Humans
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Necrosis / genetics
  • Oxidative Stress / genetics*
  • Pyruvate Dehydrogenase Complex / genetics
  • Pyruvate Dehydrogenase Complex / metabolism*
  • Reactive Oxygen Species / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics*
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Pyruvate Dehydrogenase Complex
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases