Manganese superoxide dismutase deficiency triggers mitochondrial uncoupling and the Warburg effect

Y. Xu, S. Miriyala, F. Fang, V. Bakthavatchalu, T. Noel, D. M. Schell, C. Wang, W. H. St Clair, D. K. St Clair

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.

Original languageEnglish
Pages (from-to)4229-4237
Number of pages9
JournalOncogene
Volume34
Issue number32
DOIs
StatePublished - Aug 6 2015

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health grants CA 049797 and CA 143428, and an Edward P. Evans Foundation grant to Daret K. St Clair; CA 073599 and CA 143428 to William H. St Clair; and National Nature Science Foundation of China grant 81372199 to Yong Xu. We would like to thank Dr Ronald M. Evans, Howard Hughes Medical Institute, San Diego, California 92186, USA, for providing the PPREx3-TK-luciferase construct for this study.

Publisher Copyright:
© 2015 Macmillan Publishers Limited All rights reserved.

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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