Manganese superoxide dismutase deficiency triggers mitochondrial uncoupling and the Warburg effect

• Published in: Oncogene Vol. 34; no. 32; pp. 4229 - 4237
• Main Authors: Xu, Y, Miriyala, S, Fang, F, Bakthavatchalu, V, Noel, T, Schell, D M, Wang, C, St Clair, W H, St Clair, D K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.08.2015; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 13/106; 13/109; 13/31; 13/89; 13/95; 38/39; 38/61; 38/77; 631/67/2327; 64/60; Adenosine Triphosphate - metabolism; AKT protein; Animals; Antioxidants; Apoptosis; Blotting, Western; Cancer; Carcinogenesis; Cell Biology; Cells, Cultured; Enzymes; Genetic aspects; Glycolysis; Human Genetics; Humans; Internal Medicine; Ion Channels - genetics; Ion Channels - metabolism; Lactates - metabolism; Lactic acid; Manganese; Medicine; Medicine & Public Health; Mice, Knockout; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial diseases; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Oncology; original-article; Oxidation; Phosphatidylinositol 3-Kinases - metabolism; Physiological aspects; PPAR alpha - genetics; PPAR alpha - metabolism; Protein expression; Proto-Oncogene Proteins c-akt - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; RNA Interference; Signal transduction; Signal Transduction - genetics; Superoxide dismutase; Superoxide Dismutase - deficiency; Superoxide Dismutase - genetics; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tumorigenesis; Uncoupling Protein 1; Uncoupling Protein 2; United States
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.355

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.