Manganese superoxide dismutase deficiency triggers mitochondrial uncoupling and the Warburg effect

Oncogene. 2015 Aug 6;34(32):4229-37. doi: 10.1038/onc.2014.355. Epub 2014 Nov 3.

Abstract

Manganese superoxide dismutase (MnSOD) is a mitochondrially localized primary antioxidant enzyme, known to be essential for the survival of aerobic life and to have important roles in tumorigenesis. Here, we show that MnSOD deficiency in skin tissues of MnSOD-heterozygous knockout (Sod2(+/-)) mice leads to increased expresson of uncoupling proteins (UCPs). When MnSOD is deficient, superoxide radical and its resulting reactive oxygen species (ROS) activate ligand binding to peroxisome proliferator-activated receptor alpha (PPARα), suggesting that the activation of PPARα signaling is a major mechanism underlying MnSOD-dependent UCPs expression that consequently triggers the PI3K/Akt/mTOR pathway, leading to increased aerobic glycolysis. Knockdown of UCPs and mTOR suppresses lactate production and increases ATP levels, suggesting that UCPs contribute to increased glycolysis. These results highlight the existence of a free radical-mediated mechanism that activates mitochondria uncoupling to reduce ROS production, which precedes the glycolytic adaptation described as the Warburg Effect.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Glycolysis*
  • Humans
  • Ion Channels / genetics
  • Ion Channels / metabolism
  • Lactates / metabolism
  • Mice, Knockout
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Reactive Oxygen Species / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Superoxide Dismutase / deficiency*
  • Superoxide Dismutase / genetics
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Uncoupling Protein 1
  • Uncoupling Protein 2

Substances

  • Ion Channels
  • Lactates
  • Mitochondrial Proteins
  • PPAR alpha
  • Reactive Oxygen Species
  • Uncoupling Protein 1
  • Uncoupling Protein 2
  • Adenosine Triphosphate
  • Superoxide Dismutase
  • superoxide dismutase 2
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases