Mitochondrial Reactive Oxygen Species Alicia Kowaltowski
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Mitochondrial Reactive
Oxygen Species Alicia Kowaltowski
Mitochondrial Structure
Oxidative Phosphorylation
Cytochrome c Oxidase
Loschen G, Flohe L, Chance B. Respiratory chain linked H2O2 production in pigeon heart mitochondria.FEBS Lett., 1971 18:261-264.(Effects of different respiratory states)
Boveris A, Chance B.The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen.Biochem. J., 1973 134:707-716.(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 1975 403:292-300. (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, 552:335-344.
Electron Leakage at the Respiratory Chain
Tretter and Adam-Vizi J. Neurosci. 2004, 24:7771-7778.Starkov et al. J. Neurosci. 2004, 24:7779-7788.
Dehydrogenases and Electron Leakage
H2O
O2.-
H2O2 HO.
2H+O2 .-
Fe2+ Fe3+
TPxcat
NOS
NO.Cad. Resp.
Inner Membrane
Outer Membrane
ONOO-
SOD
catalaseGPx
TPx
ROS Detected in Mitochondria
Mitochondrial NOS
Haynes et al., J. Bioenerg. Biomembr. 2004, 36:341-346.
L-arginine
L-citrullineNOS
NO.
- Alpha isoform of neuronal NOS
- Constitutive
- Regulates Complex IV
Weisiger and Fridovich J. Biol. Chem. 1973, 248:4793-4796.Sturtz et al J. Biol. Chem. 2001, 276:38084-38089.
Okado-Matsumoto and Fridovich J. Biol. Chem. 2001, 276:38388-383893
- MnSOD in the matrix, CuZnSOD in the intermembrane space
2O2-. + 2H+ H2O2 + O2
- Mutant MnSOD (-/-) animals do not survive unless treated with MnTBAP
Mitochondrial SODs
Green and O'Brien Biochim. Biophys. Acta. 1970, 197:31-39.
Levander et al. Biochem. Biophys. Res. Commun. 1974, 58:1047-1052.
H2O2 + 2GSH 2H2O + GSSGGPx
GSSG + NADPH 2GSH + NADP+Glut red.
NADP+ + NADH NADPH + NAD+Transhidr.
()
Glutathione Peroxidase/Reductase System
H2O2 + 2RSH 2H2O + RSSRTPx
RSSR + NADPH 2RSH + NADP+TR
Watabe et al. Eur. J. Biochem. 1997, 249:52-60.
2H2O2 2H2O + O2
Radi et al. J. Biol. Chem. 1991, 266:22028-22034.
Thioredoxin Peroxidase/Reductase System
Catalase
2Cyt c3+ + 2O2-. 2Cyt c2+ + 2O2
2Cyt c2+ + H2O2 + 2H+ 2Cyt c3+ + 2H2O
Cytochrome c
Skulachev FEBS Lett. 1998, 423:275-280.
Cyt c
I
II
IV
O2 + 4e- + 4H+ 2H2ONADH
SUCC
InnerMitochondrialMembrane
III
Electron Transport, OxPhos and ROS
+ + + + + + + + +++
H+ADP ATP
O2 + e- O2-. H2O2
Q
Loschen et al. FEBS Lett. 1971, 18:261-264. Korshunov et al. FEBS Lett. 1997, 416:15-18.
Mild Uncoupling Decreases ROS Release
Cyt c
I
II
IV
O2 + 4e- + 4H+ 2H2ONADH
SUCC
InnerMitochondrialMembrane
III
Electron Transport, OxPhos and ROS
+ + + + + + + + +++
H+ADP ATP
O2 + e- O2-. H2O2
Q
Negre-Salvayre et al. FASEB J. 1997, 11:809-815.
Uncoupling Proteins Regulate ROS Release
-
-
-
+
+
+
K+
- +
K+
H+
-
-
-
+
+
+
K+
ATP
MitoKATP Regulates ROS Release
cont
rol
ATP
ATP+DZXno
K
0.0
0.2
0.4
0.6
0.8
1.0
**
**
H2O
2 R
elea
se (
nmol
s . m
in-1 .
mg-1
)
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, 9:1062-1068.
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, 110:528-533.
Holmuhamedov EL, Jahangir A, Oberlin A, Komarov A, Colombini M, Terzic A. Potassium channel openers are uncoupling protonophores: implication in cardioprotection.FEBS Lett. 2004, 568:167-170.
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, 279:49883-49888.
Tissue Protection Through Uncoupling
Preconditioning and Postconditioning
wash ischemia reperfusion damage
IP damage
25 min 30 min 30 min
+ antioxidants damage
+ antioxidants
damage
Preconditioning and ROS
Vanden Hoek et al. J. Biol. Chem. 1998 273:18092-18098.
IP
Ischemic Protection
Mitochondrial ROS
mitoKATP UCP
Mild Uncoupling
ROS
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