ReviewReactive oxygen species and the brain in sleep apnea☆
Introduction
Reactive oxygen species (ROS) can be generated from various subcellular compartments, including mitochondria, the cellular membrane, lysosomes, peroxisomes, and the endoplasmic reticulum (Angermuller et al., 2009, Bedard and Krause, 2007, Droge, 2002, Kubota et al., 2010, Santos et al., 2009). While ROS production in mitochondria relies solely on the electron transport chain, it usually involves multiple enzymatic systems in other subcellular compartments. For example, NADPH oxidase (Akki et al., 2009, Bedard and Krause, 2007), xanthine oxidase (Berry and Hare, 2004), phospholipase A2 (Muralikrishna Adibhatla and Hatcher, 2006), lipoxygenases and cyclooxygenase (Droge, 2002), and cytochrome P450 (Yasui et al., 2005) have all been identified as sources of ROS in various subcellular compartments under both physiological and pathological conditions (Fig. 1). However, since mitochondria and NADPH oxidase are arguably the predominant sources of ROS in the central nervous system and have been more recently shown to play a role in intermittent hypoxia-induced neuronal deficits, the current review will focus on these two systems and their interactions. Involvement of other ROS-producing systems in sleep apnea-related neuropathology has not been thus far either explored or confirmed. However, such involvement should not be excluded and definitely warrants additional future investigation.
Section snippets
Mitochondria
Mitochondria are the major cellular source of reactive oxygen species (ROS) in most non-phagocytic cells under normal conditions. As the cellular power plant, mitochondria convert energy contained in nutrients to ATP, the universal energy currency of all biological systems, through oxidative phosphorylation. During this process, a pair of electrons is donated by NADH to complex I (NADH-ubiquinone oxidoreductase) or by FADH2 to complex II (succinate dehydrogenase) of the electron transport chain
NADPH oxidase
NADPH oxidase is a multi-subunit enzyme complex, localized in both the plasma membrane and membranes of subcellular organelles, that catalyzes electron transfer from NADPH to molecular oxygen, producing superoxide. NADPH oxidase was first identified in phagocytes where its ROS-producing function plays an essential role in non-specific host defense against microbes during phagocytosis (Lambeth, 2004). It was soon found that enzyme systems similar to the phagocyte NADPH oxidase existed in many
Cross-talk between mitochondria and the NADPH oxidase
While mitochondria and the NADPH oxidase are each capable of producing superoxide independently, emerging evidence suggests the existence of a cross-talk between the two cellular systems in which they appear to be co-stimulatory (Daiber, 2010). Several studies have shown that mitochondria may regulate superoxide production by NADPH oxidase. For example, increased NADPH oxidase activity and superoxide production induced by hypoxia or serum withdrawal were diminished by inhibition of
The clinical spectrum of SBD and OSAS
Before we address the main question, it seems appropriate to provide a quick overview of the clinical term of sleep-disordered breathing (SDB). Indeed, SDB encompasses a spectrum of respiratory disturbances during sleep, ranging from intermittent snoring to obstructive sleep apnea syndrome (OSAS). OSAS, the most severe form of SBD, affects approximately 3–5% of the general population including children, and is characterized by repeated episodes of upper airway obstruction during sleep (Lumeng
Summary
The cumulative evidence is supportive for ROS playing a major role in the deleterious effects of IH on selected CNS structures. The putative mechanisms underlying neuronal dysfunction and loss as well as reactive gliosis in animals and humans exposed to IH during sleep remain however poorly defined. Recent findings implicating NADPH oxidase and mitochondrial dysfunction as important sources of excessive ROS production in the context of IH provide a well needed impetus for accurate delineation
Conflict of interest
The authors have no conflict of interest to declare in relation to this manuscript.
Acknowledgements
DG is supported by National Institutes of Health grants HL65270 and HL086662.
References (136)
- et al.
NADPH oxidase signaling and cardiac myocyte function
J. Mol. Cell. Cardiol.
(2009) - et al.
Synchronized whole cell oscillations in mitochondrial metabolism triggered by a local release of reactive oxygen species in cardiac myocytes
J. Biol. Chem.
(2003) The sites and topology of mitochondrial superoxide production
Exp. Gerontol.
(2010)- et al.
Nutritional approaches to combat oxidative stress in Alzheimer's disease
J. Nutr. Biochem.
(2002) - et al.
Production of reactive oxygen species by mitochondria: central role of complex III
J. Biol. Chem.
(2003) - et al.
Isolating the segment of the mitochondrial electron transport chain responsible for mitochondrial damage during cardiac ischemia
Biochem. Biophys. Res. Commun.
(2010) - et al.
NADPH oxidase of human neutrophils. Subcellular localization and characterization of an arachidonate-activatable superoxide-generating system
J. Biol. Chem.
(1987) Redox signaling (cross-talk) from and to mitochondria involves mitochondrial pores and reactive oxygen species
Biochim. Biophys. Acta
(2010)- et al.
Nonezymatic formation of succinate in mitochondria under oxidative stress
Free Radic. Biol. Med.
(2006) - et al.
Intermittent hypoxic exposure during light phase induces changes in cAMP response element binding protein activity in the rat CA1 hippocampal region: water maze performance correlates
Neuroscience
(2003)
High fat/refined carbohydrate diet enhances the susceptibility to spatial learning deficits in rats exposed to intermittent hypoxia
Brain Res.
Developmental differences in cortical and hippocampal vulnerability to intermittent hypoxia in the rat
Neurosci. Lett.
Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing
Cell Metab.
Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol
J. Biol. Chem.
Partial resolution of the enzymes catalyzing oxidative phosphorylation. XV. Reverse electron transfer in the flavin-cytochrome beta region of the respiratory chain of beef heart submitochondrial particles
J. Biol. Chem.
Apocynin attenuate spatial learning deficits and oxidative responses to intermittent hypoxia
Sleep Med.
NOX1/NADPH oxidase negatively regulates nerve growth factor-induced neurite outgrowth
Free Radic. Biol. Med.
NADH-Ubiquinone oxidoreductase: substrate-dependent oxygen turnover to superoxide anion as a function of flavin mononucleotide
Mitochondrion
Effect of intermittent hypoxia on atherosclerosis in apolipoprotein E-deficient mice
Atherosclerosis
High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria
FEBS Lett.
Constitutive reactive oxygen species generation from autophagosome/lysosome in neuronal oxidative toxicity
J. Biol. Chem.
Characterization of superoxide-producing sites in isolated brain mitochondria
J. Biol. Chem.
Obstructive sleep apnoea syndrome—an oxidative stress disorder
Sleep Med. Rev.
Link between mitochondria and NADPH oxidase 1 isozyme for the sustained production of reactive oxygen species and cell death
J. Biol. Chem.
Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production
J. Biol. Chem.
HIF-1 alpha signaling is augmented during intermittent hypoxia by induction of the Nrf2 pathway in NOX1-expressing adenocarcinoma A549 cells
Free Radic. Biol. Med.
Regulated production of free radicals by the mitochondrial electron transport chain: cardiac ischemic preconditioning
Adv. Drug Deliv. Rev.
The protonmotive Q cycle: a general formulation
FEBS Lett.
Complex III releases superoxide to both sides of the inner mitochondrial membrane
J. Biol. Chem.
Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia
Free Radic. Biol. Med.
Tetrahydrobiopterin scavenges superoxide in dopaminergic neurons
J. Biol. Chem.
The p67(phox) activation domain regulates electron flow from NADPH to flavin in flavocytochrome b(558)
J. Biol. Chem.
Mitochondrial redox metabolism: aging, longevity and dietary effects
Mech. Ageing Dev.
Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase
J. Neurosci.
Alternative excitotoxic hypotheses
Neurology
Classical inhibitors of NOX NAD(P)H oxidases are not specific
Curr. Drug Metab.
Mitochondrial metabolism of reactive oxygen species
Biochemistry (Mosc.)
Peroxisomes and reactive oxygen species, a lasting challenge
Histochem. Cell Biol.
Aging, energy, and oxidative stress in neurodegenerative diseases
Ann. Neurol.
The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology
Physiol. Rev.
Neurobehavioral effects of obstructive sleep apnea: an overview and heuristic model
Curr. Opin. Pulm. Med.
Obstructive sleep apnea and the prefrontal cortex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits
J. Sleep Res.
The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production
J. Cell Biol.
Oxidative Phosphorylation, Biochemistry
Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications
J. Physiol.
Metabolic effects of the obstructive sleep apnea syndrome and cardiovascular risk
Arch. Physiol. Biochem.
Molecular pathways to neurodegeneration
Nat. Med.
The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen
Biochem. J.
The ATP synthase—a splendid molecular machine
Annu. Rev. Biochem.
A wave of reactive oxygen species (ROS)-induced ROS release in a sea of excitable mitochondria
Antioxid. Redox Signal.
Cited by (93)
Multiple Sclerosis and related disorders
2022, Handbook of Clinical NeurologyDownregulation of TSPO expression inhibits oxidative stress and maintains mitochondrial homeostasis in cardiomyocytes subjected to anoxia/reoxygenation injury
2020, Biomedicine and PharmacotherapyCitation Excerpt :ROS is a general term for oxygen free radical, singlet oxygen, hydrogen peroxide and other oxidants, majorly produced in mitochondrial metabolic reactions [6]. Thus, ROS boost is tightly related with mitochondrial homeostasis [7,8]. Furthermore, elevated ROS positively activated ROS production during reperfusion, namely ROS burst, which causes severe oxidative stress, and the opening of mitochondrial permeability transition pore (mPTP) [9].
Erythropoietin and caffeine exert similar protective impact against neonatal intermittent hypoxia: Apnea of prematurity and sex dimorphism
2019, Experimental NeurologyCitation Excerpt :The brain vulnerability to oxidative stress is further exacerbated in preterm neonates (Perrone et al., 2010). ROS are mainly produced by mitochondrial respiration and by cytosolic enzymes such as NADPH oxidase (NOX) and xanthine oxidase (Wang et al., 2010), while super oxide dismutase (SOD), glutathione peroxidase (GPX) and catalase are the main antioxidant enzymes (Lavie, 2015). Furthermore, both Epo and caffeine are potent antioxidant factors.
- ☆
This paper is part of a special issue entitled “Physiological Redox: Regulation in Respiratory, Vascular, and Neural Cells”, guest-edited by Paul T. Schumacker and Jeremy P.T. Ward.