title: Manganese superoxide dismutase deficiency triggers mitochondrial uncoupling and the Warburg effect.
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.
authors.affiliation: Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington, KY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Miriyala
authors.affiliation: Department of Radiation Medicine, University of Kentucky, Lexington, KY, USA.
authors.forename: F
authors.initials: F
authors.lastname: Fang
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington, KY, USA.
authors.forename: V
authors.initials: V
authors.lastname: Bakthavatchalu
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington, KY, USA.
authors.forename: T
authors.initials: T
authors.lastname: Noel
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington, KY, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Schnell
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Radiation Medicine, University of Kentucky, Lexington, KY, USA.
authors.forename: W H
authors.initials: WH
authors.lastname: St Clair
authors.affiliation: 1] Graduate Center for Toxicology, University of Kentucky, Lexington, KY, USA [2] Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors.forename: D K
authors.initials: DK
authors.lastname: St Clair
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D006019:Glycolysis; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000099156:Superoxide Dismutase 2
chemical_list: D000255:Adenosine Triphosphate; D007473:Ion Channels; D007773:Lactates; D024101:Mitochondrial Proteins; D047493:PPAR alpha; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D058570:TOR Serine-Threonine Kinases; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000099156:Superoxide Dismutase 2; C546843:mTOR protein, mouse