Review ArticleCross talk between mitochondria and NADPH oxidases
Introduction
Over the past several years, it has become clear that reactive oxygen species (ROS) play an important role in both physiological and pathological processes [1], [2]. Superoxide (O2•−) and hydrogen peroxide (H2O2) have been implicated in redox regulation of cell differentiation, proliferation, migration, and vasodilatation [3], [4], [5], [6]. Under normal physiological conditions, production of ROS is highly restricted to specific subcellular sites and is down-regulated by a number of negative feed-back mechanisms [7], [8], [9], [10]. Production of ROS “in the wrong place at the wrong time” or generation of ROS in excessive amounts results in oxidative stress leading to cellular dysfunction and apoptosis, which contribute to atherosclerosis [11], heart failure [12], hypertension [13], ischemia/reperfusion injury [14], cancer [15], aging [16], and neurodegeneration [17]. Although there are numerous enzyme systems that produce ROS in mammalian cells, four enzymatic systems seem to predominate. These include the NADPH oxidases [18], xanthine oxidase [19], uncoupled NO synthase [20], and the mitochondrial electron transport chain [16]. There is a substantial interplay between these sources, such that activation of one can lead to activation of the others (Fig. 1). This can lead to feed-forward processes that further augment ROS production and oxidative stress [21]. The phenomenon of ROS-induced ROS production is very well documented: H2O2 activates O2•− production by phagocytic and nonphagocytic NADPH oxidases [22]; peroxynitrite uncouples endothelial NO synthase (eNOS), switching from NO to O2•− production, and increases production of mitochondrial ROS [23], [24]; and H2O2 induces transformation of xanthine dehydrogenase into xanthine oxidase, a source of H2O2 and O2•−[25]. The interplay between specific ROS sources, however, is not clear. Cross talk between two major ROS sources, mitochondria and NADPH oxidases, is of particular interest.
Section snippets
Mitochondrial function and production of mitochondrial ROS
It is generally assumed that the major biological function of mitochondria is ATP synthesis by oxidative phosphorylation [26]. This process is based on aerobic oxidation of hydrogen and is much more efficient than anaerobic metabolism of glucose. It is based on transfer of electrons through the mitochondrial respiratory chain (Fig. 2). Electrons can be supplied by either NADH at complex I or succinate at complex II. Ubiquinone mediates electron transfer to complex III, which in turn reduces
Mitochondria-targeted antioxidants
Recent studies have demonstrated that decrease in mitochondrial ROS by overexpression of SOD2 protects against mitochondrial oxidative damage and myocardial dysfunction [67], [68], [69]. Low-molecular-weight antioxidants, such as α-tocopherol and N-acetylcysteine, also decrease mitochondrial oxidative damage in vitro [70]. In vivo, however, these traditional antioxidants have limited mitochondrial accumulation [71]. A major continued challenge, therefore, is to develop mitochondria-targeted
NADPH oxidases
NADPH oxidases are a family of enzyme complexes whose primary function is to catalyze the transfer of electrons from NADPH to molecular oxygen via their “Nox” catalytic subunit, generating O2•− and H2O2. The Nox enzymes contribute to numerous biological and pathological processes, including hearing and balance (Nox3), blood pressure regulation, inflammation, cell growth (Nox1/Nox2), and differentiation (Nox4) [86]. The Nox proteins vary in terms of their mode of activation and localization [87]
Stimulation of mitochondrial ROS by NADPH oxidases
We have previously reported that AngII increases production of mitochondrial ROS and decreases mitochondrial membrane potential, respiratory control ratio, and low-molecular-weight thiol content. Activation of NADPH oxidases is an early response of endothelial cells to AngII [114]. Angiotensin II binds to the AngII type 1 receptor, leading to rapid generation of ROS through PKC-dependent activation of NADPH oxidases. The deleterious effects of AngII on mitochondrial function are associated with
Activation of NADPH oxidases by mitochondrial ROS
It has been shown that opening of mitoKATP channels with diazoxide in rat vascular smooth muscle cells depolarized the mitochondrial membrane potential and increased cellular O2•− detected by dihydroethidium [115]. Activation of mitoKATP channels with diazoxide stimulates O2•− production on mitochondrial complex I [43]; however, dihydroethidium does not detect mitochondrial O2•−[21]. The increase in dihydroethidium fluorescence indicates O2•− production in the cytoplasm by NADPH oxidases [21].
Cross talk between mitochondria and NADPH oxidases
The data described above suggest that activation of NADPH oxidases may increase production of mitochondrial ROS and vice versa: increase in mitochondrial ROS may activate NADPH oxidases. We have suggested that this represents an ongoing feed-forward cycle. Indeed, acute treatment of AngII-stimulated cells with the mitochondria-targeted SOD mimetic mitoTEMPO reduced mitochondrial superoxide measured by MitoSOX, completely blocked the increase in NADPH oxidase activity measured in the membrane
Hypertension
Although ROS do not regulate blood pressure under normal conditions, they clearly contribute to the elevation in blood pressure in the setting of hypertension. ROS mediate the potent vasoconstrictor and hypertrophic effects of AngII and treatment with antioxidants decreases AngII-induced hypertension [126], [127]. PEG–SOD very effectively lowers blood pressure in AngII-treated rats, but not in normal rats [128]. Blood pressure is normal in mice lacking subunits of the NADPH oxidase, but these
Atherosclerosis
Oxidative modification of LDL and its transport into the subendothelial space of the arterial wall at the sites of endothelial damage are considered initiating events for atherosclerosis [132]. Oxidative modification of LDL results from the interaction of reactive oxygen species and reactive nitrogen species, produced from vascular wall cells and macrophages, with LDL. The resulting increased oxidative and nitroso-oxidative stress induces endothelial dysfunction by impairing the bioactivity of
Cancer
Oxidative stress plays an important role in malignant transformation and cancer progression [15]. The incidence of melanoma is increasing worldwide, and the prognosis for patients with high-risk or advanced metastatic melanoma remains poor despite the advances in the field [136]. As prostate cancer and aberrant changes in ROS become more common with aging, ROS signaling may play an important role in the development and progression of this malignancy. Oxidative stress is associated with several
Diabetes
Oxidative stress mediated by hyperglycemia-induced generation of ROS contributes significantly to the development and progression of diabetes and related vascular complications [144]. Michael Brownlee suggested that the mitochondrial electron transport chain plays a key role in a hyperglycemia-induced overproduction of superoxide and the development of secondary complications such as endothelial dysfunction [145]. In ρ0 endothelial cells, removal of the mitochondrial electron transport chain
Neurodegeneration
Mitochondrial oxidative stress has been implicated in cognitive longevity [150]. Human cognition depends on the ability of the central nervous system to sustain high rates of energy production continuously throughout life while maintaining a healthy internal electrochemical environment. However, the central nervous system is especially susceptible to oxidative stress. The brain contains large amounts of iron, ascorbate, glutamate (a free radical-generating excitatory neurotransmitter), and
Aging
In 1972 Denham Harman suggested that free radical damage of mitochondria can be a key determinant of the aging process [160]. It has been shown that mitochondrial dysfunction and damage of mtDNA as a result of endogenous and mitochondrial ROS play an important role in the degenerative processes [161]. Although the limitations of this hypothesis have been recently criticized by David Gems and Linda Partridge [162], there are many compelling studies demonstrating that mitochondrial O2•−
Cardiac dysfunction
Emerging evidence suggests the involvement of NADPH oxidases in cardiac physiological and pathophysiological processes [166]. Definitive evidence for the involvement of NADPH oxidases in pathological hypertrophy came from experiments in Nox2−/− mice [167]. ROS affect cellular Ca2+ regulation at several levels, notably via redox modifications of key amino acid residues involved in the function and gating properties of intracellular and plasma membrane ion channels and transporters—e.g., L-type
Future directions
The role of mitochondrial oxidative stress in pathological conditions is very well documented; however, the role of mitochondrial ROS in physiological processes and adaptive responses is less clear. It is conceivable that mitochondrial ROS affect cell proliferation, cell transformation, survival, and differentiation via interaction with NADPH oxidases [1]. The specific molecular mechanisms of cross talk between NADPH oxidases and mitochondria have to be further investigated [173]. Mitochondria
Acknowledgments
The author thanks Drs. Lula Hilenski and Anna Dikalova for assistance with manuscript preparation. This work was supported by funding from National Institutes of Health Grant HL094469.
References (174)
- et al.
Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes
Trends Biochem. Sci.
(2010) - et al.
Biphasic regulation of leukocyte superoxide generation by nitric oxide and peroxynitrite
J. Biol. Chem.
(2000) - et al.
Oxidative stress and hypertension
J. Am. Soc. Hypertens.
(2007) - et al.
Cardiac ischemia/reperfusion, aging, and redox-dependent alterations in mitochondrial function
Arch. Biochem. Biophys.
(2003) - et al.
Oxidative stress, DNA methylation and carcinogenesis
Cancer Lett.
(2008) Mitochondria, free radicals, and neurodegeneration
Curr. Opin. Neurobiol.
(1996)- et al.
H2O2-induced O2 production by a non-phagocytic NAD(P)H oxidase causes oxidant injury
J. Biol. Chem.
(2001) - et al.
Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase
J. Biol. Chem.
(2003) - et al.
Peroxynitrite reactions and formation in mitochondria
Free Radic. Biol. Med.
(2002) - et al.
Mitochondrial free radical generation, oxidative stress, and aging
Free Radic. Biol. Med.
(2000)
Respiratory enzymes in oxidative phosphorylation. III. The steady state
J. Biol. Chem.
Determination of the production of superoxide radicals and hydrogen peroxide in mitochondria
Methods Enzymol.
Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol
J. Biol. Chem.
Production of superoxide radicals and hydrogen peroxide by NADH-ubiquinone reductase and ubiquinol–cytochrome c reductase from beef-heart mitochondria
Arch. Biochem. Biophys.
The sites and topology of mitochondrial superoxide production
Exp. Gerontol.
Topology of superoxide production from different sites in the mitochondrial electron transport chain
J. Biol. Chem.
Tissue-, substrate-, and site-specific characteristics of mitochondrial reactive oxygen species generation
Free Radic. Biol. Med.
Mitochondria: regulators of signal transduction by reactive oxygen and nitrogen species
Free Radic. Biol. Med.
Mitochondria: more than just a powerhouse
Curr. Biol.
Role of oxalacetate in the regulation of mammalian succinate dehydrogenase
J. Biol. Chem.
Diphenyleneiodonium acutely inhibits reactive oxygen species production by mitochondrial complex I during reverse, but not forward electron transport
Biochim. Biophys. Acta
Redox regulation of the mitochondrial K(ATP) channel in cardioprotection
Biochim. Biophys. Acta
Antimycin A and lipopolysaccharide cause the leakage of superoxide radicals from rat liver mitochondria
Biochim. Biophys. Acta
The neuromediator glutamate, through specific substrate interactions, enhances mitochondrial ATP production and reactive oxygen species generation in nonsynaptic brain mitochondria
J. Biol. Chem.
Sites of generation of reactive oxygen species in homogenates of brain tissue determined with the use of respiratory substrates and inhibitors
Biochim. Biophys. Acta
Reaction of peroxynitrite with Mn-superoxide dismutase: role of the metal center in decomposition kinetics and nitration
J. Biol. Chem.
Effects of variation in superoxide dismutases (SOD) on oxidative stress and apoptosis in lens epithelium
Exp. Eye Res.
Mitochondrial dysfunction in cardiovascular disease
Free Radic. Biol. Med.
Protein oxidation of cytochrome C by reactive halogen species enhances its peroxidase activity
J. Biol. Chem.
Increased sensitivity of mitochondrial respiration to inhibition by nitric oxide in cardiac hypertrophy
J. Mol. Cell. Cardiol.
Mitochondrial tyrosine nitration precedes chronic allograft nephropathy
Free Radic. Biol. Med.
Rotenone model of Parkinson disease: multiple brain mitochondria dysfunctions after short term systemic rotenone intoxication
J. Biol. Chem.
Redox signalling by transcription factors NF-kappa B and AP-1 in lymphocytes
Biochem. Pharmacol.
Mitochondrial function is required for hydrogen peroxide-induced growth factor receptor transactivation and downstream signaling
J. Biol. Chem.
Human mitochondrial peroxiredoxin 5 protects from mitochondrial DNA damages induced by hydrogen peroxide
FEBS Lett.
Drug delivery to mitochondria: the key to mitochondrial medicine
Adv. Drug Deliv. Rev.
Mitochondrial targeting of electron scavenging antioxidants: regulation of selective oxidation vs random chain reactions
Adv. Drug Deliv. Rev.
A mitochondria-targeted nitroxide is reduced to its hydroxylamine by ubiquinol in mitochondria
Free Radic. Biol. Med.
Spin trapping of superoxide radicals and peroxynitrite by 1-hydroxy-3-carboxy-pyrrolidine and 1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidine and the stability of corresponding nitroxyl radicals towards biological reductants
Biochem. Biophys. Res. Commun.
Mitochondria superoxide dismutase mimetic inhibits peroxide-induced oxidative damage and apoptosis: role of mitochondrial superoxide
Free Radic. Biol. Med.
Reactive oxygen and targeted antioxidant administration in endothelial cell mitochondria
J. Biol. Chem.
Nox proteins in signal transduction
Free Radic. Biol. Med.
Distinct roles of Nox1 and Nox4 in basal and angiotensin II-stimulated superoxide and hydrogen peroxide production
Free Radic. Biol. Med.
The E-loop is involved in hydrogen peroxide formation by the NADPH oxidase Nox4
J. Biol. Chem.
NADPH oxidases: functions and pathologies in the vasculature
Arterioscler. Thromb. Vasc. Biol.
Nox4 is required for maintenance of the differentiated vascular smooth muscle cell phenotype
Arterioscler. Thromb. Vasc. Biol.
Epidermal growth factor receptor transactivation by angiotensin II requires reactive oxygen species in vascular smooth muscle cells
Arterioscler. Thromb. Vasc. Biol.
Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology
Arterioscler. Thromb. Vasc. Biol.
Akt-dependent phosphorylation of serine 1179 and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 cooperatively mediate activation of the endothelial nitric-oxide synthase by hydrogen peroxide
Mol. Pharmacol.
Interactions between ROS and AMP kinase activity in the regulation of PGC-1alpha transcription in skeletal muscle cells
Am. J. Physiol. Cell Physiol.
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