Therapeutic Photobiomodulation: Nitric Oxide and a Novel Function of Mitochondrial Cytochrome C Oxidase
Abstract: Currently, light therapies are widely used in both human and veterinarian medicine. The application of light to clinical therapeutics includes: photodynamic therapy, used to kill cancer cells; UVA therapies, used to treat a variety of skin diseases; and photobiomodulation, used to promote cell growth and recovery from injury. Photobiomodulation uses light emitting diodes (LEDs) or low energy lasers, which emit light in the visible red to near infrared range. Light in this range penetrates tissue reasonably well, lacks the carcinogenic/mutagenic properties of UV light, and acts on an endogenous photoreceptor which likely acts to initiate light-altered signaling pathways. Although early studies identified mitochondrial cytochrome c oxidase as an endogenous photoreceptor for photobiomodulation, the cellular and molecular mechanisms underlying photobiomodulation have not been clear. Three recent findings provide important new insight. First, nitric oxide has been implicated. Second, cytochrome c oxidase, an enzyme known to reduce oxygen to water at the end of the mitochondrial respiratory chain, has been shown to have a new enzymatic activity -- the reduction of nitrite to nitric oxide. This nitrite reductase activity is elevated under hypoxic conditions but also occurs under normoxia. And third, low intensity light enhances nitric oxide synthesis by cytochrome c oxidase without altering its ability to reduce oxygen. From these findings, we propose that cytochrome c oxidase functions in photobiomodulation by producing nitric oxide, a signaling molecule which can then function in both intra- and extracellular signaling pathways. We also propose that the effectiveness of photobiomodulation is under the control of tissue oxygen and nitrite levels.
It has been recognized for some time that light can affect the growth and metabolism of organisms, ranging from simple unicellular microorganisms to multi-cellular plants and mammals, and can have a variety of beneficial therapeutic effects. Indeed, the use of sunlight in heliotherapy dates as far back as 1,400 BC and has been practiced for several centuries in many different countries, including ancient Rome, Greece, and Egypt (Roetlandts, 2002). By about 1,900, light therapies had moved from the use of direct sunlight to the use of filtered sunlight and artificial light sources- fluorescent tubes, and carbon arc or quartz lamps. Early applications of light for therapeutic purposes included treatment of skin diseases and ulcers, syphilis, lupus, pellagra, wound healing, and tuberculosis. These treatments focused largely on the application of light in the UV range of the spectrum and often used UVA light in conjunction with plant extracts that contained methyloxypsoralen or 5-methoxypsoralen to treat skin diseases (Roetlandts, 1991).
Current Applications of Light Therapy
The phototubes and lamps used for early studies have all but been supplanted by lasers and LEDs and now light therapy is broadly applied to physical therapy and a variety of conditions and pathophysiological states both in human and veterinarian medicine. Applications of light to clinical therapeutics range from: (1) photodynamic therapy, used to target and kill cancer cells (Pass, 1993; Higuchi et al., 2008; 2010), to (2) UVA therapies, used to treat sclerotic skin disease (Kroft et al., 2008), and to (3) photobiomodulation [also known as: low level light or (laser) therapy (LLLT) (Karu, 1999; Hamblin and Demidova, 2006)], used to promote cell growth and recovery from injury (Karu, 1999; Zhang et al., 2003; Eells et al., 2004; Hu et al., 2007).
Photodynamic therapy makes use of light to activate exogenous photosensitive reagents which, together with oxygen, produce oxidants that kill cancer cells (Dougherty, 1987). The wavelengths and intensities of light used in photodynamic therapy are matched to the absorption spectra of the photosensitive reagent. UVA therapy increases the bioavailability of nitric oxide, via its release from subcutaneous tissue stores (e.g., nitrosothiols, nitrite) (Paunel et al., 2005; Suschek et al., 2010). The nitric oxide made available by UVA light treatment stimulates keratinocyte growth and differentiation (Krischel et al., 1998) and may play a key role in the healing of skin abrasions. Recently, the nitric oxide made available by UVA treatment has also been shown to lower systemic blood pressure (Oplander et al., 2009), perhaps by the photorelaxation of blood vessels (Furchott et al., 1961; Chaudhry et al., 1993).
In contrast to photodynamic therapy and UVA therapy, photobiomodulation uses light to affect the activity of one or more endogenous enzyme photoreceptors, which likely initiate cell signaling pathways and alter cell and tissue metabolism as well as cell proliferation. The effective wavelengths for photobiomodulation are in the visible near red to near infrared (NIR) range, between ~590-850 nm. Light in this region of the spectrum can penetrate tissues and, at the same time, lacks the carcinogenic and mutagenic properties of ultraviolet light. Several recent studies have revealed that photobiomodulation by low intensity light in this range facilitates wound and retinal healing (Conlan et al., 1996; Eells et al., 2004), improves recovery rates from ischemia by protecting cardiomyocytes from hypoxia and reoxygenation injury (Zhang et al., 2009), promotes muscle regeneration (Weiss and Oron, 1992), prevents the neurotoxic effects of cyanide and azide on neuronal cells (Wong-Riley et al., 2001; Wong-Riley et al., 2005; Liang et al., 2006), and restores axonal transport in Parkinson’s disease cybrid neurites (Trimmer et al., 2009). In addition, it has been reported that NIR light promotes cell proliferation in fibroblasts (Taniguchi et al., 2009) and endothelial cells (Chen et al., 2008), attenuates oxidative stress (Lim et al., 2008), and has neuroprotective effects in vivo against optic neuropathies brought about by mitochondrial dysfunction in a rodent model (Rojas et al., 2008). There appears to be an optimal dose (total light energy or fluence) for photobiomodulation and doses larger than the optimal value will either have a diminished or negative effect (Hamblin and Demidova, 2006; Ball et al., 2011).
Mitochondrial Cytochrome C Oxidase as a Photoreceptor for Photobiomodulation
Although the mechanisms underlying the therapeutic benefits of photobiomodulation are still incompletely understood, an important first step in understanding this phenomenon has come from the finding that cytochrome c oxidase, the terminal member of the mitochondrial electron transport chain, is a photoreceptor that mediates many, if not all, of the beneficial effects of photobiomodulation (Karu, 1999; Wong-Riley et al., 2001; Karu et al., 2004; Karu et al., 2005). Evidence that mitochondrial cytochrome c oxidase is the primary photoreceptor for photobiomodulation initially came from the finding that most of the light absorbed by cells is absorbed by mitochondrial cytochrome c oxidase (and, to a lesser extent, by other mitochondrial pigments) (Beauvoit et al., 1994), and from a determination of the action spectrum on NIR light on cell proliferation and cell attachment (Karu, 1999; Karu et al., 2005). Additional evidence for the involvement of mitochondrial cytochrome c oxidase in photobiomodulation has come from several studies with neuronal cells and tissues. These studies have demonstrated: (1) that light at 670 nm reverses the ability of tetrototoxin, a sodium channel blocker, to diminish mitochondrial cytochrome c oxidase activity in neuronal cells (Wong-Riley et al., 2001); and (2) that NIR light reverses the toxic effects of methanol on mitochondrial cytochrome c oxidase in rat retinas, resulting in improved vision (Eells et al., 2003). More direct evidence for the involvement of cytochrome c oxidase in photobiomodulation comes from studies on neuronal cell death (Wong-Riley et al., 2005). These studies examined whether inhibitors of mitochondrial cytochrome c oxidase could compete with NIR treatment. The results from these studies indicated that NIR light could protect neuronal cells from induced cell death by potassium cyanide, a potent cytochrome c oxidase inhibitor. These studies, done under normoxic conditions, also revealed that the most effective wavelengths paralleled the NIR absorption spectrum of oxidized cytochrome c oxidase. When considered together, these studies provide compelling evidence that mitochondrial cytochrome c oxidase is a primary photoreceptor for photobiomodulation.
As a photoreceptor, mitochondrial cytochrome c oxidase represents the first step in an intracellular photo-signaling pathway, and it is likely that its enzymatic activities are responsible for generating the molecules that serve to initiate a signaling cascade. Until recently, mitochondrial cytochrome c oxidase was thought to have only one enzymatic activity: the reduction of oxygen to water. This reaction occurs under normoxic conditions and involves the addition of 4 electrons and 4 protons to diatomic oxygen, according to the following reaction: 4 H+ + 4 e- + 2 O2 →H2O. This reaction has been designated Cco/H2O (Poyton et al., 2009a). During the Cco/H2O reaction, oxygen is reduced by a series of one-electron transfers which can also generate superoxide (O2-), hydrogen peroxide (H2O2), and the hydroxyl ion (OH-). Superoxide, hydrogen peroxide, and the hydroxyl radical are incompletely reduced forms of oxygen and are referred to collectively as reactive oxygen species (ROS). These ROS are produced as part of the redox chemistry of cytochrome c oxidase and are normally sequestered at the binuclear reaction center within holo-cytochrome c oxidase.
Recently, mitochondrial cytochrome c oxidase was discovered to have a second enzymatic activity: the reduction of nitrite to nitric oxide. This activity has been called Cco/NO (Poyton et al., 2009a). The rate of the Cco/NO reaction increases with nitrite concentration and with decreasing pH, findings that are consistent with the following reaction: (NO2- + Fe(II) + H+ →Fe(III) + OH-) (Castello et al., 2006, 2008). Cco/NO activity is operative at physiological nitrite concentrations (Castello et al., 2006; Ball et al., 2011) and has been detected in a variety of eukaryotes, including yeast, rat liver (Castello et al., 2006), human endothelial cells (Poyton et al., 2009b), bovine heart and calf liver (Kollau et al., 2009), plants (Igamberdiev and Hill, 2008), and algae (Tischner et al., 2004). Interestingly, some of the nitric oxide produced by Cco/NO acts inside of cells and some is released from cells (Poyton et al., 2009b). As such, the nitric oxide generated by Cco/NO is an ideal candidate for initiating signaling pathways in response to the photobiomodulation of cytochrome c oxidase.
Nitric Oxide, Cco/NO, and Photobiomodulation
Several studies have implicated nitric oxide in photobiomodulation. These range from the finding that human monocytes release nitric oxide when exposed to NIR light (Lindgard et al., 2008) to the finding that different wavelengths of NIR light have differential effects on the expression of inducible nitric oxide synthase (Moriyama et al., 2005; 2009). In a recent study, it has been reported that NIR could protect cardiomyocytes from hypoxia and reoxygenation damage, and that this protection involves nitric oxide (Zhang et al., 2009). This study also reported that not all of the nitric oxide involved is produced by nitric oxide synthases. The finding that some of the nitric oxide is not produced by nitric oxide synthases is interesting because of the recently discovered Cco/NO activity of cytochrome c oxidase. Indeed, this activity provides an alternative enzymatic source of cellular nitric oxide.
Early studies revealed that Cco/NO activity is inhibited by high oxygen concentrations and functions primarily under hypoxic conditions (Castello et al., 2006). However, more recent studies have revealed that Cco/NO activity can be modulated and functions over a wide range of oxygen concentrations. For example, studies with yeast have demonstrated that Cco/NO activity is differentially affected by the oxygen-regulated isoforms of cytochrome c oxidase (Castello et al., 2008). Cytochrome c oxidase carrying the aerobic isoform, Va, of yeast subunit V (mammalian subunit IV-1) has Cco/NO activity which is optimal at oxygen concentrations below 20 μM O2, an oxygen level that is within the hypoxic range for most tissues (van Faassen et al., 2009). In contrast, cytochrome c oxidase carrying the hypoxic oxygen regulated-subunit isoform, Vb, of yeast subunit V (mammalian subunit IV-2) has Cco/NO activity that functions at oxygen concentrations as high as 160 μM O2 (Castello et al., 2008), which is well within the normoxic range for many mammalian tissues (van Faassen et al., 2009). An elevated ratio of ADP/ATP also alters the oxygen sensitivity of Cco/NO in both yeast and mammalian mitochondria, allowing an enzyme with the aerobic oxygen-regulated cytochrome c oxidase subunit isoform to produce nitric oxide under normoxic conditions (Castello and Ball, unpublished results).
Photobiomodulation and Oxygen
Given that cytochrome c oxidase possesses two distinct enzymatic activities, Cco/H2O and Cco/NO, and can function as a “molecular switch” in response to oxygen (Poyton et al., 2009a), it is likely that the signals that initiate signaling pathways in response to light are also oxygen dependent. Hence, it becomes important to consider oxygen concentration in assessing how cytochrome c oxidase functions as a photoreceptor for photobiomodulation. Mammalian tissues experience different levels of oxygenation and it has been proposed (van Faassen et al., 2009) that oxygen concentration ranges corresponding to normoxia, hypoxia, and anoxia are 20-130 mM O2, 2-20 mM O2, and anything less than 2 mM O2, respectively. Although most mammalian tissues experience oxygen levels that are in the normoxic range it is important to note that hypoxia accompanies many disease and pathophysiological states (c.f., Peers et al., 2009; Finger and Garcia, 2010; Ng et al., 2010).
The photobiomodulation of Cco/H2O can affect normoxic cells in a few different ways. First, because light can affect the oxidation state of cytochrome c oxidase (Winterrle and Einarsdottir, 2006; Tachtsidis et al., 2007), it could also alter the conformation of the binuclear reaction center and cause the release of ROS, which may, in turn, function in cell signaling pathways (D’Autreaux and Toledano, 2007). Second, insofar as the Cco/H2O reaction plays a pivotal role in regulating cellular energy production (Poyton et al., 1988; Villani and Attardi, 2000; Piccoli et al., 2006), it is possible that some wavelengths of NIR light stimulate the turnover rate of Cco/H2O (Pastore et al., 2000) and hence electron transport through the mitochondrial respiratory chain. An accelerated rate of electron transport through the respiratory chain could have beneficial effects by increasing the rate of ATP synthesis. In addition, an accelerated rate of electron transport through the respiratory chain would be expected to reduce ROS production by respiratory complexes I and III (Poyton et al., 2009a).
Although Cco/NO can produce nitric oxide under normoxic conditions its activity is enhanced under hypoxic and anoxic conditions. Until recently, little if anything was known about photobiomodulation of Cco/NO in hypoxic cells and tissues. This has been addressed in a recent study that looked at the effects of photobiomodulation on both Cco/H2O, assayed under normoxic conditions, and Cco/NO, assayed under hypoxic and anoxic conditions (Ball et al., 2011). These studies revealed that low intensity (4 mW/cm2) broad spectrum light stimulated Cco/NO but not Cco/H2O activity and that maximal stimulation was achieved by exposure to 590 ± 14 nm light. This stimulation was observed under both normoxic and hypoxic conditions. Because low intensity 590 ± 14 nm light stimulates the Cco/NO reaction but does not affect the Cco/H2O reaction, it is unlikely that the increase in the rate of nitric oxide synthesis by Cco/NO is due to a generalized increase in the rate of electron transfer between cytochrome c and cytochrome c oxidase or an increase in an internal electron transfer step shared by the Cco/NO and Cco/H2O reactions (Ball et al., 2011). Instead, it is likely that 590 ± 14 nm light stimulates Cco/NO activity by increasing the rate of dissociation of nitric oxide from an a32+-NO complex. This is supported by previous reports that the a32+-NO complex absorbs maximally at 595-597 nm (Hayashi et al., 2007; Boelens et al., 1982) and is photosensitive when exposed to light (Boelens et al., 1982; Sarti et al., 2000). We propose that by increasing the “off rate” for nitric oxide from Cco/NO, light increases the “on rate” for nitrite on Cco/NO and hence the overall rate of new nitric oxide synthesis.
Photobiomodulation and Nitric Oxide Bioavailability — a New View
Recently, it has been proposed that photobiomodulation may increase nitric oxide bioavailability by releasing it from intracellular stores, especially heme proteins (e.g., hemoglobin or myoglobin) (Lohr et al., 2009; Shiva and Gladwin, 2009). It has also been proposed that the beneficial effect of photobiomodulation may rest on its ability to photo-dissociate nitric oxide from cytochrome c oxidase (Karu et al., 2005). Because nitric oxide inhibits mitochondrial respiration in normoxic cells, by binding to cytochrome c oxidase, photodissociation of nitric oxide would restore oxygen consumption. These explanations are applicable under normoxic conditions in which the effective wavelengths (670 nm & 830 nm) for photobiomodulation correspond to the oxidized heme a3 of cytochrome c oxidase, and in which the nitric oxide is produced predominantly by nitric oxide synthase.
The above explanations are not applicable to the hypoxic conditions that accompany many disease states because hypoxia promotes the formation of reduced cytochromes and results in acidosis that favors Cco/NO activity (Castello et al., 2006). As such, the recent finding that low intensity 590 ± 14 nm light stimulates Cco/NO activity (Ball et al., 2011) under both hypoxic and, to a lesser extent, normoxic conditions provides an alternative explanation for the increase in nitric oxide bioavailability observed during photobiomodulation. Indeed, these new findings indicate that low level light stimulates new nitric oxide synthesis from Cco/NO and does not merely release nitric oxide from pre-existing tissue stores. Because the nitric oxide produced by Cco/NO can be used both inside cells, where it functions in hypoxic signaling, and outside of cells where it may function in vasodilation and other signaling pathways (Poyton et al., 2009a; 2009b), it is likely to have a multitude of effects.
Insofar as light may have differential effects under normoxic and hypoxic conditions the challenge for the future will be to sort out the relationships between tissue oxygen levels and the beneficial effects of photobiomodulation, and to elucidate how the nitric oxide produced by Cco/NO functions in a clinically beneficial way.
The work discussed here from the authors’ laboratory was supported by Grant GM30228 from the National Institutes of Health, and a grant from Clarimedix.
The authors report no conflicts of interest.
Robert O. Poyton, Ph.D., Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA.
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[Discovery Medicine; ISSN: 1539-6509; Discov Med 11(57):154-159, February 2011.]