Nitric oxide regulates mitochondrial oxidative stress protection via the transcriptional coactivator PGC-1 (original) (raw)
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The FASEB Journal, 2006
Nitric oxide (NO) has both prooxidant and antioxidant activities in the endothelium; however, the molecular mechanisms involved are still a matter of controversy. PGC-1␣ [peroxisome proliferators-activated receptor (PPAR) ␥ coactivator 1-␣] induces the expression of several members of the mitochondrial reactive oxygen species (ROS) detoxification system. Here, we show that NO regulates this system through the modulation of PGC-1␣ expression. Short-term (<12 h) treatment of endothelial cells with NO donors down-regulates PGC-1␣ expression, whereas long-term (>24 h) treatment up-regulates it. Treatment with the NOS inhibitor L-NAME has the opposite effect. Downregulation of PGC-1␣ by NO is mediated by protein kinase G (PKG). It is blocked by the soluble guanylate cyclase (sGC) inhibitor ODQ and the PKG inhibitor KT5823, and mimicked by the cGMP analog 8-Br-cGMP. Changes in PGC-1␣ expression are in all cases paralleled by corresponding variations in the mitochondrial ROS detoxification system. Cells that transiently overexpress PGC-1␣ from the cytomeglovirus (CMV) promoter respond poorly to NO donors. Analysis of tissues from eNOS ؊/؊ mice showed reduced levels of PGC-1␣ and the mitochondrial ROS detoxification system. These data suggest that NO can regulate the mitochondrial ROS detoxification system both positively and negatively through PGC-1␣.
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 and mitochondrial biogenesis: A key to long-term regulation of cellular metabolism
Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 2005
Mitochondria, the site of oxidative energy metabolism in eukariotic cells, are a highly organised structure endowed with different enzymes and reactions localized in discrete membranes and aqueous compartments. Mitochondrial function is regulated in complex ways by several agonists and environmental conditions, through activation of specific transcription factors and signalling pathways. A key player in this scenario is nitric oxide (NO). Its binding to cytochrome c oxidase in the mitochondrial respiratory chain, which is reversible and in competition with oxygen, plays a role in acute oxygen sensing and in the cell response to hypoxia. Evidence of the last two years showed that NO has also long-term effects, leading to biogenesis of functionally active mitochondria, that complement its oxygen sensing function. Mitochondrial biogenesis is triggered by NO through activation of guanylate cyclase and generation of cyclic GMP, and yields formation of functionally active mitochondria. Thus, the combined action of NO at its two known intracellular receptors, cytochrome c oxidase and guanylate cyclase, appears to play a role in coupling energy generation with energy demand. This may explain why dysregulation of the NO signalling pathway is often associated with the pathogenesis of metabolic disorders.
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 ...
Nitric oxide signaling regulates mitochondrial number and function
Cell Death and Differentiation, 2003
Obesity affects many millions of children and adults worldwide and poses a major health problem. Weight gain results when energy intake exceeds energy expenditure. Energy can be dissipated in the form of work or heat. In order to combat obesity and associated disease, including diabetes, heart attack, and stroke, understanding how our body regulates energy balance will be of fundamental importance. Recent findings have revealed that the brain regulates energy expenditure. Environmental cues, such as cold, exercise, and food-intake signal the sympathetic nervous system to trigger the release of the hormone, noradrenaline, which in turn innervates brown adipose tissue (BAT) by binding to the b-adrenergic receptor (reviewed in Lowell and Spiegelman 1 ). BAT is the major site of adaptive thermogenesis, which protects the body from cold and controls the response to changes in diet. b-adrenergic receptor stimulation then leads to mitochondrial biogenesis (mitochondrial proliferation and activation). The mitochondrion can be viewed as a cellular furnace where fatty acids and glucose are oxidized, and energy is stored as ATP or wasted as heat, thus regulating cellular energy balance. The exact pathways that lead to mitochondrial proliferation in response to b-adrenergic receptor signaling in BAT are not entirely understood. Clues have emerged indicating that transcriptional control is implicated in this process. 2-6 Now Nisoli et al. 7 have made the intriguing discovery that the gas nitric oxide (NO) links badrenergic receptor signaling with mitochondrial biogenesis by increasing the activity of a master transcriptional regulator of the mitochondrial biogenesis program. Here we will highlight the observations made by Nisoli and colleagues and speculate on their potential implications for the study of energy metabolism, aging, and cell death.
Cell Research, 2005
Mitochondria have long been considered to be the powerhouse of the living cell, generating energy in the form of the molecule ATP via the process of oxidative phosphorylation. In the past 20 years, it has been recognised that they also play an important role in the implementation of apoptosis, or programmed cell death. More recently it has become evident that mitochondria also participate in the orchestration of cellular defence responses. At physiological concentrations, the gaseous molecule nitric oxide (NO) inhibits the mitochondrial enzyme cytochrome c oxidase (complex IV) in competition with oxygen. This interaction underlies the mitochondrial actions of NO, which range from the physiological regulation of cell respiration, through mitochondrial signalling, to the development of "metabolic hypoxia"-a situation in which, although oxygen is available, the cell is unable to utilise it.
Mitochondrial nitric oxide synthase
Frontiers in Bioscience, 2007
Mitochondria produce nitric oxide (NO) through a Ca 2Csensitive mitochondrial NO synthase (mtNOS). The NO produced by mtNOS regulates mitochondrial oxygen consumption and transmembrane potential via a reversible reaction with cytochrome c oxidase. The reaction of this NO with superoxide anion yields peroxynitrite, which irreversibly modifies susceptible targets within mitochondria and induces oxidative and/or nitrative stress. In this article, we review the current understanding of the roles of mtNOS as a crucial biochemical regulator of mitochondrial functions and attempt to reconcile apparent discrepancies in the literature on mtNOS. Discovery of mitochondrial nitric oxide synthase The discovery that the endothelium-derived relaxing factor is nitric oxide (NO) [1] opened new horizons in biomedical research. The cellular synthesis of NO is catalyzed by NO synthase (NOS) isozymes, three of which are well characterized. Although expression of these enzymes is not tissue specific, they are referred to as neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS). Each isozyme consumes L-arginine, produces equal amounts of NO and L-citrulline, and requires Ca 2C-calmodulin for activity. The activity of eNOS and nNOS are regulated tightly by alterations in Ca 2C status but, because iNOS forms a complex with calmodulin at very low concentrations of Ca 2C , its activity is not regulated by Ca 2C alterations. NO exerts a broad spectrum of functions in several system, including the cardiovascular system, PNS, CNS and immune system. These functions are mediated through the reactions of NO with targets that include hemoproteins, thiols and superoxide anions. Mitochondria possess several hemoproteins (e.g. cytochrome c oxidase), thiols (e.g. glutathione) and cysteine-containing proteins, and they are major cellular sources of superoxide anion. Consequently, mitochondria are important targets of NO and contribute to several of the biological functions of NO [2]. Several laboratories have addressed the possibility that NOS is present in mitochondria. The cross-reaction of mitochondria with antibodies to Ca 2C-sensitive eNOS was reported almost simultaneously by two laboratories. In rats, mitochondria from skeletal muscle fibers from the diaphragm [3], non-synaptosomal brain [4], and heart, skeletal muscle and kidney [5] cross-react with eNOS antibodies. Other laboratories also report an association
Mechanisms of Cell Signaling by Nitric Oxide and Peroxynitrite: From Mitochondria to MAP Kinases
Antioxidants & Redox Signaling, 2001
Many of the biological and pathological effects of nitric oxide (NO) are mediated through cell signaling pathways that are initiated by NO reacting with metalloproteins. More recently, it has been recognized that the reaction of NO with free radicals such as superoxide and the lipid peroxyl radical also has the potential to modulate redox signaling. Although it is clear that NO can exert both cytotoxic and cytoprotective actions, the focus of this overview are those reactions that could lead to protection of the cell against oxidative stress in the vasculature. This will include the induction of antioxidant defenses such as glutathione, activation of mitogen-activated protein kinases in response to blood flow, and modulation of mitochondrial function and its impact on apoptosis. Models are presented that show the increased synthesis of glutathione in response to shear stress and inhibition of cytochrome c release from mitochondria. It appears that in the vasculature NO-dependent signaling pathways are of three types: (i) those involving NO itself, leading to modulation of mitochondrial respiration and soluble guanylate cyclase; (ii) those that involve S-nitrosation, including inhibition of caspases; and (iii) autocrine signaling that involves the intracellular formation of peroxynitrite and the activation of the mitogen-activated protein kinases. Taken together, NO plays a major role in the modulation of redox cell signaling through a number of distinct pathways in a cellular setting. Antioxid. Redox Signal. 3, 215-229. 215 NITRIC OXIDE AS AN ANTIOXIDANT 217 LEVONEN ET AL. 218 NITRIC OXIDE AS AN ANTIOXIDANT 225
Nitric oxide and mitochondrial biogenesis
Journal of Cell Science, 2006
The characteristic structural organization of mitochondria is the product of synthesis of macromolecules within the mitochondria together with the import of proteins and lipids synthesized outside the organelle. Synthetic and import processes are required for mitochondrial proliferation and might also facilitate the growth of pre-existing mitochondria. Recent evidence indicates that these events are regulated in a complex way by several agonists and environmental conditions, through activation of specific signaling pathways and transcription factors. A newly discovered role of this organelle in retrograde intracellular signaling back to the nucleus has also emerged. This is likely to have far-reaching implications in development, aging, disease and environmental adaptation. Generation of nitric oxide (NO) appears to be an important player in these processes, possibly acting as a unifying molecular switch to trigger the whole mitochondrial biogenesis process. High levels of NO acutel...
Biochemical and Biophysical Research Communications, 2006
Nitric oxide (NO) is known to mediate a multitude of biological effects including inhibition of respiration at cytochrome c oxidase (COX), formation of peroxynitrite (ONOO À) by reaction with mitochondrial superoxide (O 2 ÅÀ), and S-nitrosylation of proteins. In this study, we investigated pathways of NO metabolism in lymphoblastic leukemic CEM cells in response to glutathione (GSH) depletion. We found that NO blocked mitochondrial protein thiol oxidation, membrane permeabilization, and cell death. The effects of NO were: (1) independent of respiratory chain inhibition since protection was also observed in CEM cells lacking mitochondrial DNA (q 0) which do not possess a functional respiratory chain and (2) independent of ONOO À formation since nitrotyrosine (a marker for ONOO À formation) was not detected in extracts from cells treated with NO after GSH depletion. However, NO increased the level of mitochondrial protein S-nitrosylation (SNO) determined by the Biotin Switch assay and by the release of NO from mitochondrial fractions treated with mercuric chloride (which cleaves SNO bonds to release NO). In conclusion, these results indicate that NO blocks cell death after GSH depletion by preserving the redox status of mitochondrial protein thiols probably by a mechanism that involves S-nitrosylation of mitochondrial protein thiols.