Reactions of peroxynitrite in the mitochondrial matrix 1 1 Paper dedicated to the memory of Prof. Lars Ernster, convener of ICRO-UNESCO in a series of ICRO courses in Buenos Aires (original) (raw)
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Oxidants in mitochondria: from physiology to diseases
Biochimica Et Biophysica Acta-molecular Basis of Disease, 1995
Reactive oxygen species (ROS: superoxide radical, O2-; hydrogen peroxide, H202; hydroxyl radical, OH), which arise from the univalent reduction of dioxygen are formed in mitochondria. We summarize here results which indicate that ROS, and also the radical nitrogen monoxide ('nitric oxide', NO), act as physiological modulators of some mitochondrial functions, but may also damage mitochondria. Hydrogen peroxide, which originates in mitochondria predominantly from the dismutation of superoxide, causes oxidation of mitochondrial pyridine nucleotides and thereby stimulates a specific Ca 2+ release from intact mitochondria. This release is prevented by cyclosporin A (CSA). Hydrogen peroxide thus contributes to the maintenance of cellular Ca 2÷ homeostasis. A stimulation of mitochondrial ROS production followed by an enhanced Ca 2+ release and re-uptake (Ca 2+ 'cycling') by mitochondria causes apoptosis and necrosis, and contributes to hypoxia/reperfusion injury. These kinds of cell injury can be attenuated at the mitochondrial level by CSA. When ROS are produced in excessive amounts in mitochondria nucleic acids, proteins, and lipids are extensively modified by oxidation. Physiological (sub-micromolar) concentrations of NO potently and reversibly deenergize mitochondria at oxygen tensions that prevail in cells by transiently binding to cytochrome oxidase. This is paralleled by mitochondrial Ca 2÷ release and uptake. Higher NO concentrations or prolonged exposure of cells to NO causes their death. It is concluded that ROS and NO are important physiological reactants in mitochondria and become toxic only when present in excessive amounts.
Differential Inhibitory Action of Nitric Oxide and Peroxynitrite on Mitochondrial Electron Transport
Archives of Biochemistry and Biophysics, 1996
Nitric oxide ( • NO, nitrogen monoxide), 2 an endoge-Various authors have suggested that nitric oxide nously synthesized radical intermediate, plays an im-( • NO) exerts cytotoxic effects through the inhibition of portant physiologic role in different organ systems (1cellular respiration. Indeed, in intact cells • NO inhibits 3). In spite of the physiologic role of • NO, it has become glutamate-malate (complex I) as well as succinate evident that it can mediate cytotoxic actions either dur-(complex II)-supported mitochondrial electron transing the normal defensive function of neutrophils and port, without affecting TMPD/ascorbate (complex IV)macrophages toward target cells (4-6) or by excess prodependent respiration. However, experiments in our duction in tissues undergoing diverse pathological situlab using isolated rat heart mitochondria indicated ations (7-9).
Peroxynitrite reactions and formation in mitochondria
Free Radical Biology and Medicine, 2002
Mitochondria constitute a primary locus for the intracellular formation and reactions of peroxynitrite, and these interactions are recognized to contribute to the biological and pathological effects of both nitric oxide ( • NO) and peroxynitrite. Extra-or intramitochondrially formed peroxynitrite can diffuse through mitochondrial compartments and undergo fast direct and free radical-dependent target molecule reactions. These processes result in oxidation, nitration, and nitrosation of critical components in the matrix, inner and outer membrane, and intermembrane space. Mitochondrial scavenging and repair systems for peroxynitrite-dependent oxidative modifications operate but they can be overwhelmed under enhanced cellular • NO formation as well as under conditions that lead to augmented superoxide formation by the electron transport chain. Peroxynitrite can lead to alterations in mitochondrial energy and calcium homeostasis and promote the opening of the permeability transition pore. The effects of peroxynitrite in mitochondrial physiology can be largely rationalized based on the reactivities of peroxynitrite and peroxynitrite-derived carbonate, nitrogen dioxide, and hydroxyl radicals with critical protein amino acids and transition metal centers of key mitochondrial proteins. In this review we analyze (i) the existing evidence for the intramitochondrial formation and reactions of peroxynitrite, (ii) the key reactions and fate of peroxynitrite in mitochondria, and (iii) their impact in mitochondrial physiology and signaling of cell death.
Biochemical Journal, 2001
This study was aimed at assessing the effects of long-term exposure to NO of respiratory activities in mitochondria from different tissues (with different ubiquinol contents), under conditions that either promote or prevent the formation of peroxynitrite. Mitochondria and submitochondrial particles isolated from rat heart, liver and brain were exposed either to a steady-state concentration or to a bolus addition of NO. NO induced the mitochondrial production of superoxide anions, hydrogen peroxide and peroxynitrite, the latter shown by nitration of mitochondrial proteins. Long-term incubation of mitochondrial membranes with NO resulted in a persistent inhibition of NADH:cytochrome c reductase activity, interpreted as inhibition of NADH:ubiquinone reductase (Complex I) activity, whereas succinate:cytochrome c reductase activity, including Complex II and Complex III electron transfer, remained unaffected. This selective effect of NO and derived species was partially prevented by superoxide dismutase and uric acid. In addition, peroxynitrite mimicked the effect of NO, including tyrosine nitration of some Complex I proteins. These results seem to indicate that the inhibition of NADH:ubiquinone reductase (Complex I) activity depends on the NO-induced generation of superoxide radical and peroxynitrite and that Complex I is selectively sensitive to peroxynitrite. Inhibition of Complex I activity by peroxynitrite may have critical implications for energy supply in tissues such as the brain, whose mitochondrial function depends largely on the channelling of reducing equivalents through Complex I.
doi:10.1155/2012/571067 Review Article The Chemical Interplay between Nitric Oxide and Mitochondrial
2015
Copyright © 2012 Paolo Sarti et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Nitric oxide (NO) reacts with Complex I and cytochrome c oxidase (CcOX, Complex IV), inducing detrimental or cytoprotective eects. Two alternative reaction pathways (PWs) have been described whereby NO reacts with CcOX, producing either a relatively labile nitrite-bound derivative (CcOX-NO2 −, PW1) or a more stable nitrosyl-derivative (CcOX-NO, PW2). The two derivatives are both inhibited, displaying dierent persistency and O2 competitiveness. In the mitochondrion, during turnover with O2, one pathway prevails over the other one depending on NO, cytochrome c2+ and O2 concentration. High cytochrome c2+, and low O2 proved to be crucial in favoring CcOX nitrosylation, whereas under-standard cell-culture conditions formation of the nitrite ...
Biochimica Et Biophysica Acta-bioenergetics, 2003
Mitochondrial cytochrome oxidase is competitively and reversibly inhibited by inhibitors that bind to ferrous heme, such as carbon monoxide and nitric oxide. In the case of nitric oxide, nanomolar levels inhibit cytochrome oxidase by competing with oxygen at the enzyme's heme -copper active site. This raises the K m for cellular respiration into the physiological range. This effect is readily reversible and may be a physiological control mechanism. Here we show that a number of in vitro and in vivo conditions result in an irreversible increase in the oxygen K m . These include: treatment of the purified enzyme with peroxynitrite or high (AM) levels of nitric oxide; treatment of the endothelial-derived cell line, b.End5, with NO; activation of astrocytes by cytokines; reperfusion injury in the gerbil brain. Studies of cell respiration that fail to vary the oxygen concentration systematically are therefore likely to significantly underestimate the degree of irreversible damage to cytochrome oxidase. D
Superoxide production by mitochondria in the presence of nitric oxide forms peroxynitrite
IUBMB Life, 1996
The mitochondrial respiratory chain continually produces superoxide leading to high levels of mitochondrial oxidative stress. This oxidative damage has been attributed to the formation of hydroxyl radicals and hydrogen peroxide from superoxide. Alternatively, mitochondrial superoxide may react with nitric oxide forming the potent oxidant peroxynitrite, thus damaging mitochondrial protein, lipid and DNA. To test this hypothesis we induced mitochondrial superoxide formation in the presence of nitric oxide. Here we demonstrate that mitochondrial superoxide reacts with nitric oxide to tbrm peroxynitfite, suggesting that mitochondria may be a significant intracellular source of peroxynitrite.
Journal of Neural Transmission, 2002
3-Nitrotyrosine (3-NT) is a specific marker of protein nitration by peroxynitrite (ONOO Ϫ ) produced from nitric oxide and superoxide. Increase in 3-NT containing protein (3-NT protein) was reported in brains from patients with some neurodegenerative disorders and aging. In this paper, intracellular localization of 3-NT protein was examined in dopaminergic SH-SY5Y cells using the selective antibody against protein-bound 3-NT. 3-NT protein was detected in plasma membrane/nucleus and mitochondria fractions, and interestingly in polypeptide composition of mitochondrial complex I. ONOO Ϫ -generating SIN-1 induced apoptotic cell death with concomitant increase in 3-NT protein and reduction in mitochondrial ATP synthesis. In addition, an inhibitor of proteasomes, carbobenzoxy-L-isoleucyl-γ-t-butyl-Lglutamyl-L-alanyl-L-leucinal, enhanced the effects of ONOO Ϫ . These results suggest that ONOO Ϫ may induce mitochondrial dysfunction and cell death in neurons through nitration of mitochondrial complex I subunits.