Review ArticleCarbon monoxide, reactive oxygen signaling, and oxidative stress
Introduction
Carbon monoxide (CO) is a primordial gas that people have long equated with incomplete combustion and silent asphyxiation. However, since the 1950s CO also has been recognized as an endogenous product of heme metabolism [1] and today its importance is appreciated more prevalently in biology than even a decade ago [2]. It is known, for instance, that CO is produced and metabolized by organisms from prokaryotes to mammals and serves as an important intrinsic signaling molecule predominantly via its propensity to bind to reduced transition-metal centers in heme proteins [3], [4], [5].
In the bacterial world, CO is a central metabolite in the anaerobic carbon cycle, and some aerobic chemotrophs even utilize it as their sole source of energy [6], [7]. In these microbes, as well as in the endosymbiotic mitochondria of eukaryotes, CO undergoes oxidation to CO2 [8]. In higher animals, especially vertebrates, CO is recognized as a by-product of the normal enzymatic degradation of heme by the heme oxygenases (HO) [9]. The excess CO is carried by hemoglobin to the lungs for excretion, while that in the cell services physiological processes from platelet aggregation [10] to vasodilation [11] to apoptosis—including both pro-and antiapoptotic effects [12], [13], [14], [15], [16], [17], [18]. Moreover, the HO/CO system is part of the integrated defense against cell stress including heat shock, heavy metals, ROS, lipopolysaccharide (LPS), and other inflammatory processes [19], [20], [21], [22], [23].
The gaps in our understanding CO biology exist mainly in the biochemical mechanisms of CO signaling in integrated systems—specifically when and how CO’s effects are conveyed as physiological signals based on interactions with iron-or other metallo-proteins that contain active-site transition metals. Perhaps most widely appreciated in this regard is CO’s activation of guanylate cyclase (GC), a pivotal heme enzyme whose product, guanosine 3,5-cyclic monophosphate GMP (cGMP), is involved in vascular tone, gene regulation, neurotransmission, and many other cellular processes [24], [25], [26], [27]. CO’s capacity to activate GC, however, is much weaker than is its gaseous alternative, nitric oxide (NO), which dominates cGMP-dependent cell signaling [28].
Apart from its high affinity for reduced transition metals such as Fe2+, CO is notably unreactive in biological systems, as is the ferrous-carbonyl, which is dissipated slowly by displacement of CO with molecular O2 or by oxygenation of CO to CO2 [8]. Nevertheless, CO does not go unattended physiologically, for its binding to reduced transition metal centers is relatively tight, especially among heme proteins for which molecular O2 is the preferred ligand [29]. The formation of metal-CO complexes generates diverse biological effects ranging from those where a specific enzyme is inhibited and the substrate accumulates to those that redirect electrons and lead to reactive oxygen and nitrogen species (RNS) formation. Indeed, NO does induce CO production through up-regulation of HO-1 mRNA and protein, thereby increasing the potential for the interaction of CO with reduced iron and influencing NO signaling independently of GC [30], [31], [32], [33], [34]. Moreover, it has been proposed that CO and NO may in some cases bind different sides of active heme moieties [35].
Although modest in number, each CO reaction is potentially important in both cell signaling and oxidative stress, and thus contributes to the theme of this overview, which also places special emphasis on how CO induces adaptive responses to assist mammalian systems in the tolerance of oxidative stress. A discussion of the basic physiological chemistry of CO, O2, and transition metal centers, however, is not intended, and the reader is referred to earlier publications for that information [4], [36], [37], [38].
Section snippets
The realm of CO— Physiology, adaptation, and toxicity
From the outset, it is important to place the responses to CO in vivo in line with archetypal physiology. In other words, in order to understand CO biology, core physiological processes that are tightly regulated spatially and temporally need to be differentiated from secondary or adaptive responses to CO arising from interference with physiological reactions or due to secondary ROS or RNS generation. As CO concentration rises, specificity of effect is dissipated, analogous to the progressive
Tissue and cellular CO concentrations
A fundamental factor in understanding the effects of CO from the perspective of oxidation-reduction (redox) chemistry is to know how much CO cells and tissues contain, produce normally, and take up exogenously, as well as the extent to which CO concentration varies under different types of stress. Because endogenous HO activity and heme turnover rates are difficult to quantify, it is useful to measure quasi-steady-state CO concentrations in cells and tissues using sensitive analytical
Heme protein interference by CO
The lugubrious biology of CO involves functional interference with various heme proteins, most importantly, binding ferrous heme centers on a competitive basis with molecular oxygen (O2). The binding is defined by the Warburg partition coefficient—the ratio of CO to O2 at which half the reactive sites are occupied by CO [4]. It is widely known that CO avidly binds hemoglobin’s ferrous heme moieties with an affinity of some 200 times that of molecular O2, thereby interfering with O2 carriage by
Endogenous CO production
As noted earlier, CO is an important endogenous gas synthesized by the heme oxygenases—enzymes that catalyze the rate-limiting step in heme degradation. Two main isoforms, HO-1 and HO-2, are fairly well understood while the status of a putative third (HO-3) is uncertain [2], [62]. HO breaks the alpha-methene carbon bond of the porphyrin ring using NADPH and molecular O2 in a reaction that releases equimolar amounts of biliverdin, iron, and CO. In mammalian cells, biliverdin is rapidly converted
CO and signaling through mitochondrial H2O2 production
For most of the 80 plus years since CO was first identified as a respiratory inhibitor [37] and the nearly 20 years since it was shown to bind to cytochrome c oxidase in vivo [88] mitochondrial CO effects in living tissues were considered minor because the a3 heme is primarily in the oxidized state. However, even at physiological PO2, CO does bind cytochrome oxidase, as some a3 does remain in the reduced state, especially in metabolically active tissues like the brain and the heart. Moreover,
CO and nonmitochondrial ROS signaling
ROS-dependent signaling, of course, also occurs via nonmitochondrial sources, perhaps most notably via the family of NADPH oxidase (Nox) and Duox enzymes that generate ROS in various tissues under physiological circumstances [115]. The Nox enzymes are di-heme, flavin-adenine dinucleotide-containing membrane proteins that catalyze the NAD(P)H-dependent single electron reduction of O2 to superoxide anion. CO binding to Nox cytochrome b558 moiety has been demonstrated, although the affinity is low
CO and NO
Earlier it was noted that both CO and NO activate the GC system by binding the active heme and enhancing cGMP production. Although NO is decidedly more potent than CO in activating GC, for instance, in vasodilation, [130] CO does operate in the system under specific physiological conditions; for instance, by regulating vascular smooth muscle cell proliferation in hypoxia [131]. This is an example of a GC-mediated physiological process apart from vasodilation that may be activated by CO,
Conclusions
The biological significance of and interest in carbon monoxide is mounting, but apart from its high affinity for reduced transition metals, especially heme-iron, CO is surprisingly unreactive—as is the ferrous-carbonyl moiety. CO does form relatively tight complexes with heme proteins for which molecular O2 is the preferred ligand, and this chemistry is responsible for the diverse physiological, adaptive, and toxic effects of the gas. Over the past few years, it has become increasingly apparent
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