Mitochondrial Reactive Oxygen Species Alicia Kowaltowski.

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Presentation transcript:

Mitochondrial Reactive Oxygen Species Alicia Kowaltowski

Mitochondrial Structure

Oxidative Phosphorylation

Cytochrome c Oxidase

Loschen G, Flohe L, Chance B. Respiratory chain linked H 2 O 2 production in pigeon heart mitochondria. FEBS Lett., : (Effects of different respiratory states) Boveris A, Chance B. The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem. J., : (Effects of respiratory inhibitors rotenone and antimycin) Dionisi O, Galeotti T, Terranova T, Azzi A. Superoxide radicals and hydrogen peroxide formation in mitochondria from normal and neoplastic tissues. Biochim. Biophys. Acta : (Detection of superoxide radicals) Mitochondrial Reactive Oxygen Species Formation

Nicholls and Ferguson, Bioenergetics 3, Academic Press, 2004 Complex I

Reverse Electron Transfer Nicholls and Ferguson, Bioenergetics 3, Academic Press, 2004

Complex III Nicholls and Ferguson, Bioenergetics 3, Academic Press, 2004

Turrens JF, J. Physiol. 2003, 552: Electron Leakage at the Respiratory Chain

Tretter and Adam-Vizi J. Neurosci. 2004, 24: Starkov et al. J. Neurosci. 2004, 24: Dehydrogenases and Electron Leakage

H2OH2O O 2.- H2O2H2O2 HO. 2H + O 2.- Fe 2+ Fe 3+ TPxcat NOS NO. Cad. Resp. Inner Membrane Outer Membrane ONOO - SOD catalase GPx TPx ROS Detected in Mitochondria

Mitochondrial NOS Haynes et al., J. Bioenerg. Biomembr. 2004, 36: L-arginine L-citrulline NOS NO. - Alpha isoform of neuronal NOS - Constitutive - Regulates Complex IV

Weisiger and Fridovich J. Biol. Chem. 1973, 248: Sturtz et al J. Biol. Chem. 2001, 276: Okado-Matsumoto and Fridovich J. Biol. Chem. 2001, 276: MnSOD in the matrix, CuZnSOD in the intermembrane space 2O H + H 2 O 2 + O 2 - Mutant MnSOD (-/-) animals do not survive unless treated with MnTBAP Mitochondrial SODs

Green and O'Brien Biochim. Biophys. Acta. 1970, 197: Levander et al. Biochem. Biophys. Res. Commun. 1974, 58: H 2 O 2 + 2GSH 2H 2 O + GSSG GPx GSSG + NADPH 2GSH + NADP + Glut red. NADP + + NADH NADPH + NAD + Transhidr. (  ) Glutathione Peroxidase/Reductase System

H 2 O 2 + 2RSH2H 2 O + RSSR TPx RSSR + NADPH2RSH + NADP + TR Watabe et al. Eur. J. Biochem. 1997, 249: H 2 O 2 2H 2 O + O 2 Radi et al. J. Biol. Chem. 1991, 266: Thioredoxin Peroxidase/Reductase System Catalase

2Cyt c O Cyt c O 2 2Cyt c 2+ + H 2 O 2 + 2H + 2Cyt c H 2 O Cytochrome c Skulachev FEBS Lett. 1998, 423:

Cyt c I II IV O 2 + 4e - + 4H + 2H 2 O NADH SUCC Inner Mitochondrial Membrane III Electron Transport, OxPhos and ROS H+H+ ADP ATP O 2 + e - O 2 -. H 2 O 2 Q

Loschen et al. FEBS Lett. 1971, 18: Korshunov et al. FEBS Lett. 1997, 416: Mild Uncoupling Decreases ROS Release

Cyt c I II IV O 2 + 4e - + 4H + 2H 2 O NADH SUCC Inner Mitochondrial Membrane III Electron Transport, OxPhos and ROS H+H+ ADP ATP O 2 + e - O 2 -. H 2 O 2 Q

Negre-Salvayre et al. FASEB J. 1997, 11: Uncoupling Proteins Regulate ROS Release

K+K+ -+ K+K+ H+H K+K+ ATP MitoK ATP Regulates ROS Release Ferranti et al., 2003, FEBS Letts 536:51-5

Mattiasson G, Shamloo M, Gido G, Mathi K, Tomasevic G, Yi S, Warden CH, Castilho RF, Melcher T, Gonzalez-Zulueta M, Nikolich K, Wieloch T. Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat. Med. 2003, 9: Hoerter J, Gonzalez-Barroso MD, Couplan E, Mateo P, Gelly C, Cassard-Doulcier AM, Diolez P, Bouillaud F. Mitochondrial uncoupling protein 1 expressed in the heart of transgenic mice protects against ischemic- reperfusion damage. Circulation 2004, 110: Holmuhamedov EL, Jahangir A, Oberlin A, Komarov A, Colombini M, Terzic A. Potassium channel openers are uncoupling protonophores: implication in cardioprotection. FEBS Lett. 2004, 568: Barros MH, Bandy B, Tahara EB, Kowaltowski AJ. Higher respiratory activity decreases mitochondrial reactive oxygen release and increases life span in Saccharomyces cerevisiae. J Biol Chem. 2004, 279: Tissue Protection Through Uncoupling

Preconditioning and Postconditioning washischemiareperfusion  damage IP  damage 25 min30 min + antioxidants  damage + antioxidants  damage

Preconditioning and ROS Vanden Hoek et al. J. Biol. Chem :

IP Ischemic Protection  Mitochondrial ROS mitoK ATP UCP Mild Uncoupling  ROS