Cross talk between mitochondria and NADPH oxidases

doi:10.1016/j.freeradbiomed.2011.06.033

Free Radical Biology and Medicine

Volume 51, Issue 7, 1 October 2011, Pages 1289-1301

https://doi.org/10.1016/j.freeradbiomed.2011.06.033 Get rights and content

Abstract

Reactive oxygen species (ROS) play an important role in physiological and pathological processes. In recent years, a feed-forward regulation of the ROS sources has been reported. The interactions between the main cellular sources of ROS, such as mitochondria and NADPH oxidases, however, remain obscure. This work summarizes the latest findings on the role of cross talk between mitochondria and NADPH oxidases in pathophysiological processes. Mitochondria have the highest levels of antioxidants in the cell and play an important role in the maintenance of cellular redox status, thereby acting as an ROS and redox sink and limiting NADPH oxidase activity. Mitochondria, however, are not only a target for ROS produced by NADPH oxidase but also a significant source of ROS, which under certain conditions may stimulate NADPH oxidases. This cross talk between mitochondria and NADPH oxidases, therefore, may represent a feed-forward vicious cycle of ROS production, which can be pharmacologically targeted under conditions of oxidative stress. It has been demonstrated that mitochondria-targeted antioxidants break this vicious cycle, inhibiting ROS production by mitochondria and reducing NADPH oxidase activity. This may provide a novel strategy for treatment of many pathological conditions including aging, atherosclerosis, diabetes, hypertension, and degenerative neurological disorders in which mitochondrial oxidative stress seems to play a role. It is conceivable that the use of mitochondria-targeted treatments would be effective in these conditions.

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 mitoK_ATP channels with diazoxide in rat vascular smooth muscle cells depolarized the mitochondrial membrane potential and increased cellular O₂^•− detected by dihydroethidium [115]. Activation of mitoK_ATP 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.

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Review ArticleCross talk between mitochondria and NADPH oxidases

Abstract

Introduction

Section snippets

Mitochondrial function and production of mitochondrial ROS

Mitochondria-targeted antioxidants

NADPH oxidases

Stimulation of mitochondrial ROS by NADPH oxidases

Activation of NADPH oxidases by mitochondrial ROS

Cross talk between mitochondria and NADPH oxidases

Hypertension

Atherosclerosis

Cancer

Diabetes

Neurodegeneration

Aging

Cardiac dysfunction

Future directions

Acknowledgments

Trends Biochem. Sci.

J. Biol. Chem.

J. Am. Soc. Hypertens.

Arch. Biochem. Biophys.

Cancer Lett.

Curr. Opin. Neurobiol.

J. Biol. Chem.

J. Biol. Chem.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

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Methods Enzymol.

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Arch. Biochem. Biophys.

Exp. Gerontol.

J. Biol. Chem.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Curr. Biol.

J. Biol. Chem.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Biochim. Biophys. Acta

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Biochem. Pharmacol.

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FEBS Lett.

Adv. Drug Deliv. Rev.

Adv. Drug Deliv. Rev.

Free Radic. Biol. Med.

Biochem. Biophys. Res. Commun.

Free Radic. Biol. Med.

J. Biol. Chem.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

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.

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Review Article
Cross talk between mitochondria and NADPH oxidases