title: Peroxynitrite induced mitochondrial biogenesis following MnSOD knockdown in normal rat kidney (NRK) cells.
abstract: Superoxide is widely regarded as the primary reactive oxygen species (ROS) which initiates downstream oxidative stress. Increased oxidative stress contributes, in part, to many disease conditions such as cancer, atherosclerosis, ischemia/reperfusion, diabetes, aging, and neurodegeneration. Manganese superoxide dismutase (MnSOD) catalyzes the dismutation of superoxide into hydrogen peroxide which can then be further detoxified by other antioxidant enzymes. MnSOD is critical in maintaining the normal function of mitochondria, thus its inactivation is thought to lead to compromised mitochondria. Previously, our laboratory observed increased mitochondrial biogenesis in a novel kidney-specific MnSOD knockout mouse. The current study used transient siRNA mediated MnSOD knockdown of normal rat kidney (NRK) cells as the in vitro model, and confirmed functional mitochondrial biogenesis evidenced by increased PGC1α expression, mitochondrial DNA copy numbers and integrity, electron transport chain protein CORE II, mitochondrial mass, oxygen consumption rate, and overall ATP production. Further mechanistic studies using mitoquinone (MitoQ), a mitochondria-targeted antioxidant and L-NAME, a nitric oxide synthase (NOS) inhibitor demonstrated that peroxynitrite (at low micromolar levels) induced mitochondrial biogenesis. These findings provide the first evidence that low levels of peroxynitrite can initiate a protective signaling cascade involving mitochondrial biogenesis which may help to restore mitochondrial function following transient MnSOD inactivation.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Marine
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Krager
authors.affiliation: Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Nukhet
authors.initials: N
authors.lastname: Aykin-Burns
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Lee Ann
authors.initials: LA
authors.lastname: Macmillan-Crow
mesh_terms: D000818:Animals; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000378:metabolism; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D007668:Kidney / Q000166:cytology* / Q000378:metabolism*; D008928:Mitochondria / Q000502:physiology*; D008954:Models, Biological; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology; D000099156:Superoxide Dismutase 2
chemical_list: D004272:DNA, Mitochondrial; D045222:Electron Transport Chain Complex Proteins; D019331:NG-Nitroarginine Methyl Ester; D009943:Organophosphorus Compounds; D030421:Peroxynitrous Acid; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D014451:Ubiquinone; D000099156:Superoxide Dismutase 2; C429014:mitoquinone
keywords: Mitochondrial biogenesis; MnSOD; Peroxynitrite; Respiration; mtDNA; siRNA