Oxidants in mitochondria: from physiology to diseases (original) (raw)
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Archives of Biochemistry and Biophysics, 1996
Nitric oxide (rNO) released by S-nitrosoglutathione peroxide anion; hydrogen peroxide. (GSNO) inhibited enzymatic activities of rat heart mitochondrial membranes. Cytochrome oxidase activity was inhibited to one-half at an effective rNO concentration of 0.1 mM, while succinate-and NADH-cyto-Nitric oxide (rNO) 2 is an endogenous free radical chrome-c reductase activities were half-maximally informed in a variety of cell types by NO-synthase by hibited at 0.3 mM rNO. Submitochondrial particles oxidation of L-arginine to L-citrulline (1). A function of treated with rNO (either from GSNO or from a pure rNO as a signal-transducing molecule has been desolution) showed increased O 0 2 and H 2 O 2 production scribed in endothelium and brain (2). In addition, rNO when supplemented with succinate alone, at rates that cytotoxic properties are considered as part of the nonwere comparable to those of control particles with specific immune response of activated macrophages added succinate and antimycin. Rat heart mitochonand neutrophils (3). dria treated with rNO also showed increased H 2 O 2 pro-Toxic effects of rNO, particularly by interfering with duction. Cytochrome spectra and decreased enzymatic activities in the presence of rNO are consistent with oxidative metabolism (4) or iron homeostasis , have a multiple inhibition of mitochondrial electron trans-been reported. Beckman (6) indicated that endothelial fer at cytochrome oxidase and at the ubiquinone-cytoinjury may arise from formation of peroxynitrite anion chrome b region of the respiratory chain, the latter (ONOO 0 ), the product of the diffusion-controlled reacleading to the increased O 0 2 production. Electrochemition between two molecules with unpaired electrons, cal detection showed that the buildup of a rNO concensuperoxide anion (O 0 2 ) and rNO. Peroxynitrite anion tration from GSNO was interrupted by submitochonhas been reported to produce membrane lipoperoxidadrial particles supplemented with succinate and antition (7) and sulfhydryl oxidation (8). Moreover, Radi et mycin and was restored by addition of superoxide al. (9) have reported oxidative damage to the electron dismutase. The inhibitory effect of rNO on cytochrome transport chain and the ATPase activity of rat heart oxidase was also prevented under the same conditions. mitochondria at biologically relevant ONOO 0 concen-Apparently, mitochondrial O 0 2 reacts with rNO to form trations (9) and that ONOO 0 reacts with isolated pig peroxynitrite and, by removing rNO, reactivates the aconitase, resulting in an irreversible loss of enzymatic previously inhibited cytochrome oxidase. It is sugactivity (10). gested that, at physiological concentrations of rNO, On the other hand, Cleeter et al. (11) reported that inhibition of electron transfer, rNO-induced O 0 2 pronitric oxide generated by S-nitrosoglutathione (GSNO) duction, and ONOO 0 formation participate in the reguproduces a reversible inhibition of respiration and cytolatory control of mitochondrial oxygen uptake. ᭧ 1996 Academic Press, Inc. 2 Abbreviations used: rNO, nitric oxide; ONOO 0 , peroxynitrite 1 To whom correspondence and reprint requests should be ad-anion; O 0 2
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 ...
International Journal of Cell Biology, 2012
Nitric oxide (NO) reacts with Complex I and cytochrome c oxidase (CcOX, Complex IV), inducing detrimental or cytoprotective effects. Two alternative reaction pathways (PWs) have been described whereby NO reacts with CcOX, producing either a relatively labile nitrite-bound derivative (CcOX-NO 2 − , PW1) or a more stable nitrosyl-derivative (CcOX-NO, PW2). The two derivatives are both inhibited, displaying different persistency and O 2 competitiveness. In the mitochondrion, during turnover with O 2 , one pathway prevails over the other one depending on NO, cytochrome c 2+ and O 2 concentration. High cytochrome c 2+ , and low O 2 proved to be crucial in favoring CcOX nitrosylation, whereas under-standard cell-culture conditions formation of the nitrite derivative prevails. All together, these findings suggest that NO can modulate physiologically the mitochondrial respiratory/OXPHOS efficiency, eventually being converted to nitrite by CcOX, without cell detrimental effects. It is worthy to point out that nitrite, far from being a simple oxidation byproduct, represents a source of NO particularly important in view of the NO cell homeostasis, the NO production depends on the NO synthases whose activity is controlled by different stimuli/effectors; relevant to its bioavailability, NO is also produced by recycling cell/body nitrite. Bioenergetic parameters, such as mitochondrial ΔΨ, lactate, and ATP production, have been assayed in several cell lines, in the presence of endogenous or exogenous NO and the evidence collected suggests a crucial interplay between CcOX and NO with important energetic implications.
Nitric Oxide, 2012
Nitrosyl ruthenium complexes are promising NO donor agents with numerous advantages for the biologic applications of NO. We have characterized the NO release from the nitrosyl ruthenium complex [Ru(NO 2 )(bpy) 2 (4-pic)] + (I) and the reactive oxygen/nitrogen species (ROS/RNS)-mediated NO actions on isolated rat liver mitochondria. The results indicated that oxidation of mitochondrial NADH promotes NO release from (I) in a manner mediated by NO 2 formation (at neutral pH) as in mammalian cells, followed by an oxygen atom transfer mechanism (OAT). The NO released from (I) uncoupled mitochondria at low concentrations/incubation times and inhibited the respiratory chain at high concentrations/incubation times. In the presence of ROS generated by mitochondria NO gave rise to peroxynitrite, which, in turn, inhibited the respiratory chain and oxidized membrane protein-thiols to elicit a Ca 2+ -independent mitochondrial permeability transition; this process was only partially inhibited by cyclosporine-A, almost fully inhibited by the thiol reagent N-ethylmaleimide (NEM) and fully inhibited by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO). These actions correlated with the release of cytochrome c from isolated mitochondria as detected by Western blotting analysis. These events, typically involved in cell necrosis and/or apoptosis denote a potential specific action of (I) and analogs against tumor cells via mitochondria-mediated processes.
Effects of NO on mitochondrial function in cardiomyocytes: pathophysiological relevance
Cardiovascular …, 2006
Although the specific roles of nitric oxide (NO) in the heart in general and on cardiac mitochondria in particular remain controversial, it is now clear that both endogenous and exogenous sources of NO exert important modulatory effects on mitochondrial function. There is also growing evidence that NO can be produced within the mitochondria themselves. NO can influence respiratory activity, both through direct effects on the respiratory chain or indirectly via modulation of mitochondrial calcium accumulation. At pathological concentrations, NO can cause irreversible alterations in respiratory function and can also interact with reactive oxygen species (ROS) to form reactive nitrogen species, which may further impair mitochondrial respiration and can even lead to opening of the mitochondrial permeability transition pore and cell death. Diabetes, aging, myocardial ischemia, and heart failure have all been associated with altered ROS generation, which can alter the delicate regulatory balance of effects of NO in the mitochondria. As NO competes with oxygen at cytochrome oxidase, it can be argued that experiments exploring the roles of NO on mitochondrial respiration should be performed at physiological (i.e. relatively low) oxygen tensions. Improvements in techniques, and a gradual appreciation of the many potential pitfalls in studying mitochondrial NO, are leading to a recognition of the role of NO in the regulation of mitochondrial function in the heart in health and disease.
Mechanisms of the interaction of nitroxyl with mitochondria
Biochemical Journal, 2004
It is now thought that NO • (nitric oxide) and its redox congeners may play a role in the physiological regulation of mitochondrial function. The inhibition of cytochrome c oxidase by NO • is characterized as being reversible and oxygen dependent. In contrast, peroxynitrite, the product of the reaction of NO • with superoxide, irreversibly inhibits several of the respiratory complexes. However, little is known about the effects of HNO (nitroxyl) on mitochondrial function. This is especially important, since HNO has been shown to be more cytotoxic than NO • , may potentially be generated in vivo, and elicits biological responses with some of the characteristics of NO and peroxynitrite. In the present study, we present evidence that isolated mitochondria, in the absence or presence of substrate, convert HNO into NO • by a process that is dependent on mitochondrial concentration as well as the concentration of the HNO donor Angeli's salt. In addition, HNO is able to inhibit mitochondrial respiration through the inhibition of complexes I and II, most probably via modification of specific cysteine residues in the proteins. Using a proteomics approach, extensive modification of mitochondrial protein thiols was demonstrated. From these data it is evident that HNO interacts with mitochondria through mechanisms distinct from those of either NO • or peroxynitrite, including the generation of NO • , the modification of thiols and the inhibition of complexes I and II.
Production of Nitric Oxide by Mitochondria
Journal of Biological Chemistry, 1998
The production of NO. by mitochondria was investigated by electron paramagnetic resonance using the spin-trapping technique, and by the oxidation of oxymyoglobin. Percoll-purified rat liver mitochondria exhibited a negligible contamination with other subcellular fractions (1-4%) and high degree of functionality (respiratory control ratio = 5-6). Toluene-permeabilized mitochondria, mitochondrial homogenates, and a crude preparation of nitric oxide synthase (NOS) incubated with the spin trap N-methyl-D-glucamine-dithiocarbamate-FeII produced a signal ascribed to the NO. spin adduct (g = 2.04; aN = 12.5 G). The intensity of the signal increased with time, protein concentration, and L-Arg, and decreased with the addition of the NOS inhibitor NG-monomethyl-L-arginine. Intact mitochondria, mitochondrial homogenates, and submitochondrial particles produced NO. (followed by the oxidation of oxymyoglobin) at rates of 1.4, 4.9, and 7.1 nmol NO. x (min.mg protein)-1, respectively, with a Km for L-Arg of 5-7 microM. Comparison of the rates of NO. production obtained with homogenates and submitochondrial particles indicated that most of the enzymatic activity was localized in the mitochondrial inner membrane. This study demonstrates that mitochondria are a source of NO., the production of which may effect energy metabolism, O2 consumption, and O2 free radical formation.
Mitochondria as Targets of Apoptosis Regulation by Nitric Oxide
IUBMB Life, 2004
In addition to their vital role as the cell's power stations, mitochondria exert an important function in apoptosis. In response to most if not all apoptosis inducers, mitochondrial membranes are permeabilized, leading to the release of potentially toxic proteins, mostly from the intermembrane space to the rest of the cells. Such pro-apoptotic intermembrane proteins include the caspaseindependent death effector AIF, as well as cytochrome c, which can trigger the activation of caspases, once it has reached the cytosol. The mitochondrial permeabilization process can be induced by a variety of different xenobiotics, via a direct effect on mitochondrial membranes. Alternatively, mitochondrial permeabilization can be induced by endogenous second messengers, which are elicited in response to stress. The permeabilization process is controlled by the mitochondrial permeability transition pore complex (PTPC), by proteins of the Bcl-2/Bax family, as well as by lipids and metabolites. Nitric oxide (NO) is one of the second messengers that can trigger apoptosis by inducing mitochondrial membrane permeabilization. This effect may involve a direct effect on the PTPC and/or indirect effects secondary to the NO-mediated inhibition of oxidative phosphorylation. This has far-reaching implications for the pathophysiology of NO. IUBMB Life, 55: 613-616, 2003