Friend or foe? Carbon monoxide and the mitochondria.

Abstract

PHYSIOLOGY OF CARBON MONOXIDE The longstanding perception of the gas carbon monoxide (CO) as an odorless and colorless “silent killer” began to attract the attention of the public with the arrival of the industrial age in the beginning of the twentieth century (Douglas et al., 1912). In fact, carbon monoxide has been present in all societies since the discovery of fire, yet it was John Haldane in the early part of the twentieth century that declared CO a lethal poison based on his investigations of mine disasters. American Indians knew that in addition to warmth, gathering around a fire brought calming and tranquil effects, something we now attribute to neuroactive properties of the gas. Poisonings from exhaust certainly continue to pose significant problems, as it did in the coal mine explosions, but it remains unclear why the>500 other molecules that emerge from combustion, many of which are carcinogens, are largely ignored, yet pose just as great a risk as CO. It was not until the late 1960’s that endogenous production of CO was discovered as a result of the catabolism of heme (Sjostrand, 1949; Coburn et al., 1963), suggesting a physiological role for this simple, diatomic gas. Decades after these findings were reported, investigators noted that levels of CO were significantly elevated in the exhaled breath of hospitalized patients (Vos et al., 2009; Cheng et al., 2010; James et al., 2010; Zhang et al., 2010). The illnesses were wide-ranging, yet it was clear that CO levels would decrease as the pathology resolved. How then can it be explained that CO is toxic if the body generates it physiologically and even more puzzling, generates more when in a compromised state? The answer may lie in the ancient organelle known as the mitochondria, an evolutionary endosymbiont originating from proteobacteria whose singular responsibility is to generate energy for the cell. It relies principally on the presence of gases in the elegant transfer of electrons among the oxidases contained within its membranes. The targets for CO are ostensibly clear. CO binds rapidly and with high affinity to heme-containing proteins such as hemoglobin, the mitochondria oxidases or the enzymes necessary for reactive oxygen species generation. CO competes with oxygen transport and cellular respiration and it is perhaps in this primitive symbiotic organelle, among the numerous hemoprotein complexes competing with the other bioactive gases including nitric oxide, oxygen, hydrogen sulfide and carbon dioxide that CO integrates itself and impacts cellular physiology. The body of evidence supporting a physiological role for CO is immense and continues to move forward as CO is being evaluated in ongoing clinical trials (www.clinicaltrials. gov, Identifier: NCT 01727167, 00094406, 00122694, 01214187, 01050712, 01050933, 01523548, and 00531856). The endogenous generation of CO as described by Tenhunen et al. (1968) occurs through the enzymatic degradation of heme by the heme oxygenases, enzymes present in all cells that convert heme into biliverdin, iron and CO. Like CO, it has become undeniably clear that each catalytic product has important physiological functions beyond serving as byproducts. Two isoforms of heme oxygenase exist: heme oxygenase 1 (Hmox-1), which is expressed ubiquitously and is highly inducible by an array of stimuli, and the constitutive heme oxygenase-2 (Hmox-2) isoform, predominantly expressed in neurons, the testes, and the vasculature. Induction of HO1 has proven to be a strong cytoprotectant while deficiency in HO-1 leads to aggravated disease states, even in humans (Poss and Tonegawa, 1997; Otterbein et al., 1999; Park et al., 2007; Tsuchihashi et al., 2007; Chen et al., 2009; Wang et al., 2009, 2012; Yin et al., 2010; Ferenbach et al., 2011; Ogawa et al., 2011; Zhang et al., 2012).