Nils Schallner
Leo E. Otterbein- 1Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- 2Department of Anesthesiology and Intensive Care Medicine, University Medical Center Freiburg, Freiburg, Germany
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 endo-symbiont 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 HO-1 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).
CO as a Therapeutic Agent
There is compelling pre-clinical data proving the salutary effects of exogenous CO application. (Motterlini and Otterbein, 2010) CO has been shown to regulate immune responses (Freitas et al., 2006), cell survival (Song et al., 2003) and regeneration (Lin et al., 2009; Lakkisto et al., 2010) as well as proliferation (Wegiel et al., 2013). CO is homeodynamic in that it serves the need of the tissue. There are reports that it is both anti- and pro-inflammatory (Lee et al., 2007; Beckman et al., 2009), pro- and anti-apoptotic (Song et al., 2004; Vieira et al., 2008) and pro- and anti-proliferative (Otterbein et al., 2003; Kuramitsu et al., 2011). One of the primary sites in the body where CO is believed to be most toxic is the brain and this is based on weak studies with lack of rigor and proper controls. CO is clearly neuroprotective in various neuronal injury models (Vieira et al., 2008; Zeynalov and Dore, 2009; Wang et al., 2011; Yabluchanskiy et al., 2012; Schallner et al., 2013) and extensive safety trials in humans have been completed without a single sign of toxicity at carboxyhemoglobin levels of 12–15% (Mayr et al., 2005; Bathoorn et al., 2007). Most importantly, no negative influence on cognitive function was detected. Collectively, the clinical testing is safe with quantitative delivery of inhaled CO relative to body weight and independent of the respiratory rate has also been developed (Motterlini and Otterbein, 2010). The challenges of establishing CO as a gaseous pharmaceutical triggered an onslaught of research surrounding alternative routes of CO application. Carbon Monoxide Releasing Molecules (CO-RMs) emerged in 2002 pioneered by Roberto Motterlini (Motterlini et al., 2002). CO-saturated pegylated hemoglobins have emerged that also modulate inflammation and vaso-occlusion in murine models of sickle cell anemia (Belcher et al., 2013). These CO carriers, or pro-drugs, release CO following well-defined kinetics and have been characterized to deliver CO to target tissues in several in vitro(Clark et al., 2003; Motterlini et al., 2005; Bani-Hani et al., 2006; Megias et al., 2007; Urquhart et al., 2007) and in vivo (Tayem et al., 2006; De Backer et al., 2009; Tsoyi et al., 2009; Vadori et al., 2009) studies, exerting biological effects much like inhaled gas (Bani-Hani et al., 2006; Yabluchanskiy et al., 2012).
CO and the Mitochondria
Despite profound pre-clinical evidence of efficacy, the molecular mechanisms by which CO exerts its protective effects in a diverse array of animal models remains poorly characterized with numerous and confounding molecular targets described (Motterlini and Otterbein, 2010). The high affinity for heme makes any cellular heme-containing protein a potential target for CO, including soluble guanylate cyclase (sGC) (Verma et al., 1993; Schallner et al., 2013), NO-synthase (Zuckerbraun et al., 2003; Marazioti et al., 2011), NADPH oxidase (Taille et al., 2005) and NPAS-2 (Dioum et al., 2002) among a multitude of others. While a unifying signature is lacking, the single-most implicated target is the mitochondria. This seems paradoxical at first sight since inhibition of mitochondrial respiration via CO binding to components of the mitochondrial electron transfer chain, has been looked at as being responsible for the toxicity seen after CO poisoning. Against this dogma, however, CO exposure clearly influences cellular bioenergetics in the context of salutary effects, paradoxically increasing O2 bioavailability and consumption, which in turn reduces injury-related organ damage (Tsui et al., 2007; Lancel et al., 2009). CO increases mitochondrial generation of reactive oxygen species (Chin et al., 2007; Zuckerbraun et al., 2007) and mitochondrial biogenesis, (Suliman et al., 2007; Piantadosi et al., 2008) which likely go hand-in-hand to influence the vast array of cellular downstream targets that have been linked to the beneficial effects of CO (Motterlini and Otterbein, 2010). We speculate that CO alters oxygen sensing and exerts a “pseudo-hypoxic” state, providing a powerful cellular impact toward re-generation and increasing the cellular energy supply that leads to improved survival in the presence of cell stress and injury.
Conclusions and Perspective
The name mitochondria originated from the Greek “mitos” meaning thread and “chondros” meaning granule, which referred to their structural appearance. They were first called “bioblasts” which is perhaps a more accurate designation giving the impression of explosive behavior while generating critical energy for the cell. Mitochondria are comprised of lipid bilayers and proteins like other cellular compartments including the Golgi, endoplasmic reticulum and the nucleus. The mitochondria rely to a large extent on the interrelationships among the gases, primarily O2 and CO2. These gases serve as the fundamental molecules involved in the energy-transduction system that ultimately results in generation of life-sustaining ATP. It has become clear, however that O2 and CO2 are not alone in dictating cellular physiologic and pathophysiologic responses. Much like the complexities of signal transduction, gene regulation and metabolic pathways, the cellular gases CO and its sister gases NO and H2S are critically integrated into the function of mitochondria and therein the overall health of the organism.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
Grants: German Research Foundation (DFG) SCHA1838/2-1 to Nils Schallner. We thank the Julie Henry Fund at the Transplant Center of the BIDMC for their support. Leo E. Otterbein has a visiting professorship at Aston University, Birmingham, UK.
References
Bani-Hani, M. G., Greenstein, D., Mann, B. E., Green, C. J., and Motterlini, R. (2006). Modulation of thrombin-induced neuroinflammation in bv-2 microglia by carbon monoxide-releasing molecule 3. J. Pharmacol. Exp. Ther. 318, 1315–1322. doi: 10.1124/jpet.106.104729
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Bathoorn, E., Slebos, D. J., Postma, D. S., Koeter, G. H., van Oosterhout, A. J., van der Toorn, M., et al. (2007). Anti-inflammatory effects of inhaled carbon monoxide in patients with copd: a pilot study. Eur. Respir. J. 30, 1131–1137. doi: 10.1183/09031936.00163206
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Beckman, J. D., Belcher, J. D., Vineyard, J. V., Chen, C., Nguyen, J., Nwaneri, M. O., et al. (2009). Inhaled carbon monoxide reduces leukocytosis in a murine model of sickle cell disease. Am. J. Physiol. Heart Circ. Physiol. 297, H1243–H1253. doi: 10.1152/ajpheart.00327.2009
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Belcher, J. D., Young, M., Chen, C., Nguyen, J., Burhop, K., Tran, P., et al. (2013). Mp4co, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of ho-1, inflammation, and vaso-occlusion in transgenic sickle mice. Blood 122, 2757–2764. doi: 10.1182/blood-2013-02-486282
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Chen, B., Guo, L., Fan, C., Bolisetty, S., Joseph, R., Wright, M. M., et al. (2009). Carbon monoxide rescues heme oxygenase-1-deficient mice from arterial thrombosis in allogeneic aortic transplantation. Am. J. Pathol. 175, 422–429. doi: 10.2353/ajpath.2009.081033
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Cheng, S., Lyass, A., Massaro, J. M., O'Connor, G. T., Keaney, J. F. Jr., and Vasan, R. S. (2010). Exhaled carbon monoxide and risk of metabolic syndrome and cardiovascular disease in the community. Circulation 122, 1470–1477. doi: 10.1161/CIRCULATIONAHA.110.941013
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Chin, B. Y., Jiang, G., Wegiel, B., Wang, H. J., Macdonald, T., Zhang, X. C., et al. (2007). Hypoxia-inducible factor 1alpha stabilization by carbon monoxide results in cytoprotective preconditioning. Proc. Natl. Acad. Sci. U.S.A. 104, 5109–5114. doi: 10.1073/pnas.0609611104
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Clark, J. E., Naughton, P., Shurey, S., Green, C. J., Johnson, T. R., Mann, B. E., et al. (2003). Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule. Circ. Res. 93, e2–e8. doi: 10.1161/01.RES.0000084381.86567.08
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Coburn, R. F., Blakemore, W. S., and Forster, R. E. (1963). Endogenous carbon monoxide production in man. J. Clin. Invest. 42, 1172–1178. doi: 10.1172/JCI104802
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
De Backer, O., Elinck, E., Blanckaert, B., Leybaert, L., Motterlini, R., and Lefebvre, R. A. (2009). Water-soluble co-releasing molecules reduce the development of postoperative ileus via modulation of mapk/ho-1 signalling and reduction of oxidative stress. Gut 58, 347–356. doi: 10.1136/gut.2008.155481
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Dioum, E. M., Rutter, J., Tuckerman, J. R., Gonzalez, G., Gilles-Gonzalez, M. A., and McKnight, S. L. (2002). Npas2: a gas-responsive transcription factor. Science 298, 2385–2387. doi: 10.1126/science.1078456
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Douglas, C. G., Haldane, J. S., and Haldane, J. B. (1912). The laws of combination of haemoglobin with carbon monoxide and oxygen. J. Physiol. 44, 275–304. doi: 10.1113/jphysiol.1912.sp001517
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Ferenbach, D. A., Nkejabega, N. C., McKay, J., Choudhary, A. K., Vernon, M. A., Beesley, M. F., et al. (2011). The induction of macrophage hemeoxygenase-1 is protective during acute kidney injury in aging mice. Kidney Int. 79, 966–976. doi: 10.1038/ki.2010.535
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Freitas, A., Alves-Filho, J. C., Secco, D. D., Neto, A. F., Ferreira, S. H., Barja-Fidalgo, C., et al. (2006). Heme oxygenase/carbon monoxide-biliverdin pathway down regulates neutrophil rolling, adhesion and migration in acute inflammation. Br. J. Pharmacol. 149, 345–354. doi: 10.1038/sj.bjp.0706882
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
James, E. B., Vreman, H. J., Wong, R. J., Stevenson, D. K., Vichinsky, E., Schumacher, L., et al. (2010). Elevated exhaled carbon monoxide concentration in hemoglobinopathies and its relation to red blood cell transfusion therapy. Pediatr. Hematol. Oncol. 27, 112–121. doi: 10.3109/08880010903536227
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Kuramitsu, K., Gallo, D., Yoon, M., Chin, B. Y., Csizmadia, E., Hanto, D. W., et al. (2011). Carbon monoxide enhances early liver regeneration in mice after hepatectomy. Hepatology 53, 2016–2026. doi: 10.1002/hep.24317
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Lakkisto, P., Kyto, V., Forsten, H., Siren, J. M., Segersvard, H., Voipio-Pulkki, L. M., et al. (2010). Heme oxygenase-1 and carbon monoxide promote neovascularization after myocardial infarction by modulating the expression of hif-1alpha, sdf-1alpha and vegf-b. Eur. J. Pharmacol. 635, 156–164. doi: 10.1016/j.ejphar.2010.02.050
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Lancel, S., Hassoun, S. M., Favory, R., Decoster, B., Motterlini, R., and Neviere, R. (2009). Carbon monoxide rescues mice from lethal sepsis by supporting mitochondrial energetic metabolism and activating mitochondrial biogenesis. J. Pharmacol. Exp. Ther. 329, 641–648. doi: 10.1124/jpet.108.148049
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Lee, S. S., Gao, W., Mazzola, S., Thomas, M. N., Csizmadia, E., Otterbein, L. E., et al. (2007). Heme oxygenase-1, carbon monoxide, and bilirubin induce tolerance in recipients toward islet allografts by modulating t regulatory cells. FASEB J. 21, 3450–3457. doi: 10.1096/fj.07-8472com
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Lin, H. H., Chen, Y. H., Yet, S. F., and Chau, L. Y. (2009). After vascular injury, heme oxygenase-1/carbon monoxide enhances re-endothelialization via promoting mobilization of circulating endothelial progenitor cells. J. Thromb. Haemost. 7, 1401–1408. doi: 10.1111/j.1538-7836.2009.03478.x
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Marazioti, A., Bucci, M., Coletta, C., Vellecco, V., Baskaran, P., Szabo, C., et al. (2011). Inhibition of nitric oxide-stimulated vasorelaxation by carbon monoxide-releasing molecules. Arterioscler. Thromb. Vasc. Biol. 31, 2570–2576. doi: 10.1161/ATVBAHA.111.229039
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Mayr, F. B., Spiel, A., Leitner, J., Marsik, C., Germann, P., Ullrich, R., et al. (2005). Effects of carbon monoxide inhalation during experimental endotoxemia in humans. Am. J. Respir. Crit. Care Med. 171, 354–360. doi: 10.1164/rccm.200404-446OC
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Megias, J., Busserolles, J., and Alcaraz, M. J. (2007). The carbon monoxide-releasing molecule corm-2 inhibits the inflammatory response induced by cytokines in caco-2 cells. Br. J. Pharmacol. 150, 977–986. doi: 10.1038/sj.bjp.0707184
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Motterlini, R., Clark, J. E., Foresti, R., Sarathchandra, P., Mann, B. E., and Green, C. J. (2002). Carbon monoxide-releasing molecules: characterization of biochemical and vascular activities. Circ. Res. 90, E17–E24. doi: 10.1161/hh0202.104530
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Motterlini, R., and Otterbein, L. E. (2010). The therapeutic potential of carbon monoxide. Nat. Rev. Drug Discov. 9, 728–743. doi: 10.1038/nrd3228
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Motterlini, R., Sawle, P., Hammad, J., Bains, S., Alberto, R., Foresti, R., et al. (2005). Corm-a1: a new pharmacologically active carbon monoxide-releasing molecule. FASEB J. 19, 284–286. doi: 10.1096/fj.04-2169fje
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Ogawa, T., Hanggi, D., Wu, Y., Michiue, H., Tomizawa, K., Ono, S., et al. (2011). Protein therapy using heme-oxygenase-1 fused to a polyarginine transduction domain attenuates cerebral vasospasm after experimental subarachnoid hemorrhage. J. Cereb. Blood Flow Metab. 31, 2231–2242. doi: 10.1038/jcbfm.2011.87
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Otterbein, L. E., Kolls, J. K., Mantell, L. L., Cook, J. L., Alam, J., and Choi, A. M. (1999). Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury. J. Clin. Invest. 103, 1047–1054. doi: 10.1172/JCI5342
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Otterbein, L. E., Zuckerbraun, B. S., Haga, M., Liu, F., Song, R., Usheva, A., et al. (2003). Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat. Med. 9, 183–190. doi: 10.1038/nm817
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Park, M. K., Kim, C. H., Kim, Y. M., Kang, Y. J., Kim, H. J., Kim, H. J., et al. (2007). Akt-dependent heme oxygenase-1 induction by ns-398 in c6 glial cells: a potential role for co in prevention of oxidative damage from hypoxia. Neuropharmacology 53, 542–551. doi: 10.1016/j.neuropharm.2007.06.022
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Piantadosi, C. A., Carraway, M. S., Babiker, A., and Suliman, H. B. (2008). Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ. Res. 103, 1232–1240. doi: 10.1161/01.RES.0000338597.71702.ad
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Poss, K. D., and Tonegawa, S. (1997). Reduced stress defense in heme oxygenase 1-deficient cells. Proc. Natl. Acad. Sci. U.S.A. 94, 10925–10930. doi: 10.1073/pnas.94.20.10925
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Schallner, N., Romao, C. C., Biermann, J., Lagreze, W. A., Otterbein, L. E., Buerkle, H., et al. (2013). Carbon monoxide abrogates ischemic insult to neuronal cells via the soluble guanylate cyclase-cgmp pathway. PLoS ONE 8:e60672. doi: 10.1371/journal.pone.0060672
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Sjostrand, T. (1949). Endogenous formation of carbon monoxide in man. Nature 164, 580. doi: 10.1038/164580a0
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Song, R., Kubo, M., Morse, D., Zhou, Z., Zhang, X., Dauber, J. H., et al. (2003). Carbon monoxide induces cytoprotection in rat orthotopic lung transplantation via anti-inflammatory and anti-apoptotic effects. Am. J. Pathol. 163, 231–242. doi: 10.1016/S0002-9440(10)63646-2
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Song, R., Zhou, Z., Kim, P. K., Shapiro, R. A., Liu, F., Ferran, C., et al. (2004). Carbon monoxide promotes fas/cd95-induced apoptosis in jurkat cells. J. Biol. Chem. 279, 44327–44334. doi: 10.1074/jbc.M406105200
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Suliman, H. B., Carraway, M. S., Ali, A. S., Reynolds, C. M., Welty-Wolf, K. E., and Piantadosi, C. A. (2007). The co/ho system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy. J. Clin. Invest. 117, 3730–3741. doi: 10.1172/JCI32967
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Taille, C., El-Benna, J., Lanone, S., Boczkowski, J., and Motterlini, R. (2005). Mitochondrial respiratory chain and nad(p)h oxidase are targets for the antiproliferative effect of carbon monoxide in human airway smooth muscle. J. Biol. Chem. 280, 25350–25360. doi: 10.1074/jbc.M503512200
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Tayem, Y., Johnson, T. R., Mann, B. E., Green, C. J., and Motterlini, R. (2006). Protection against cisplatin-induced nephrotoxicity by a carbon monoxide-releasing molecule. Am. J. Physiol. Renal Physiol. 290, F789–F794. doi: 10.1152/ajprenal.00363.2005
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Tenhunen, R., Marver, H. S., and Schmid, R. (1968). The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc. Natl. Acad. Sci. U.S.A. 61, 748–755. doi: 10.1073/pnas.61.2.748
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Tsoyi, K., Ha, Y. M., Kim, Y. M., Lee, Y. S., Kim, H. J., Kim, H. J., et al. (2009). Activation of ppar-gamma by carbon monoxide from corm-2 leads to the inhibition of inos but not cox-2 expression in lps-stimulated macrophages. Inflammation 32, 364–371. doi: 10.1007/s10753-009-9144-0
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Tsuchihashi, S., Zhai, Y., Bo, Q., Busuttil, R. W., and Kupiec-Weglinski, J. W. (2007). Heme oxygenase-1 mediated cytoprotection against liver ischemia and reperfusion injury: inhibition of type-1 interferon signaling. Transplantation 83, 1628–1634. doi: 10.1097/01.tp.0000266917.39958.47
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Tsui, T. Y., Obed, A., Siu, Y. T., Yet, S. F., Prantl, L., Schlitt, H. J., et al. (2007). Carbon monoxide inhalation rescues mice from fulminant hepatitis through improving hepatic energy metabolism. Shock 27, 165–171. doi: 10.1097/01.shk.0000239781.71516.61
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Urquhart, P., Rosignoli, G., Cooper, D., Motterlini, R., and Perretti, M. (2007). Carbon monoxide-releasing molecules modulate leukocyte-endothelial interactions under flow. J. Pharmacol. Exp. Ther. 321, 656–662. doi: 10.1124/jpet.106.117218
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Vadori, M., Seveso, M., Besenzon, F., Bosio, E., Tognato, E., Fante, F., et al. (2009). In vitro and in vivo effects of the carbon monoxide-releasing molecule, corm-3, in the xenogeneic pig-to-primate context. Xenotransplantation 16, 99–114. doi: 10.1111/j.1399-3089.2009.00521.x
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Verma, A., Hirsch, D. J., Glatt, C. E., Ronnett, G. V., and Snyder, S. H. (1993). Carbon monoxide: a putative neural messenger. Science 259, 381–384. doi: 10.1126/science.7678352
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Vieira, H. L., Queiroga, C. S., and Alves, P. M. (2008). Pre-conditioning induced by carbon monoxide provides neuronal protection against apoptosis. J. Neurochem. 107, 375–384. doi: 10.1111/j.1471-4159.2008.05610.x
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Vos, R., Cordemans, C., Vanaudenaerde, B. M., De Vleeschauwer, S. I., Schoonis, A., Van Raemdonck, D. E., et al. (2009). Exhaled carbon monoxide as a noninvasive marker of airway neutrophilia after lung transplantation. Transplantation 87, 1579–1583. doi: 10.1097/TP.0b013e3181a4e69c
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Wang, B., Cao, W., Biswal, S., and Dore, S. (2011). Carbon monoxide-activated nrf2 pathway leads to protection against permanent focal cerebral ischemia. Stroke 42, 2605–2610. doi: 10.1161/STROKEAHA.110.607101
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Wang, H. Q., Xu, Y. X., and Zhu, C. Q. (2012). Upregulation of heme oxygenase-1 by acteoside through erk and pi3 k/akt pathway confer neuroprotection against beta-amyloid-induced neurotoxicity. Neurotox. Res. 21, 368–378. doi: 10.1007/s12640-011-9292-5
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Wang, X. M., Kim, H. P., Nakahira, K., Ryter, S. W., and Choi, A. M. (2009). The heme oxygenase-1/carbon monoxide pathway suppresses tlr4 signaling by regulating the interaction of tlr4 with caveolin-1. J. Immunol. 182, 3809–3818. doi: 10.4049/jimmunol.0712437
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Wegiel, B., Gallo, D., Csizmadia, E., Harris, C., Belcher, J., Vercellotti, G. M., et al. (2013). Carbon monoxide expedites metabolic exhaustion to inhibit tumor growth. Cancer Res. 73, 7009–7021. doi: 10.1158/0008-5472.CAN-13-1075
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Yabluchanskiy, A., Sawle, P., Homer-Vanniasinkam, S., Green, C. J., Foresti, R., and Motterlini, R. (2012). Corm-3, a carbon monoxide-releasing molecule, alters the inflammatory response and reduces brain damage in a rat model of hemorrhagic stroke. Crit. Care Med. 40, 544–552. doi: 10.1097/CCM.0b013e31822f0d64
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Yin, H., Li, X., Gong, Q., Jin, X., Gu, H., Yuan, B., et al. (2010). Heme oxygenase-1 upregulation improves lipopolysaccharide-induced acute lung injury involving suppression of macrophage migration inhibitory factor. Mol. Immunol. 47, 2443–2449. doi: 10.1016/j.molimm.2010.06.013
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Zeynalov, E., and Dore, S. (2009). Low doses of carbon monoxide protect against experimental focal brain ischemia. Neurotox. Res. 15, 133–137. doi: 10.1007/s12640-009-9014-4
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Zhang, F., Wang, S., Zhang, M., Weng, Z., Li, P., Gan, Y., et al. (2012). Pharmacological induction of heme oxygenase-1 by a triterpenoid protects neurons against ischemic injury. Stroke 43, 1390–1397. doi: 10.1161/STROKEAHA.111.647420
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Zhang, J., Yao, X., Yu, R., Bai, J., Sun, Y., Huang, M., et al. (2010). Exhaled carbon monoxide in asthmatics: a meta-analysis. Respir. Res. 11:50. doi: 10.1186/1465-9921-11-50
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Zuckerbraun, B. S., Billiar, T. R., Otterbein, S. L., Kim, P. K., Liu, F., Choi, A. M., et al. (2003). Carbon monoxide protects against liver failure through nitric oxide-induced heme oxygenase 1. J. Exp. Med. 198, 1707–1716. doi: 10.1084/jem.20031003
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Zuckerbraun, B. S., Chin, B. Y., Bilban, M., D'Avila, J. C., Rao, J., Billiar, T. R., et al. (2007). Carbon monoxide signals via inhibition of cytochrome c oxidase and generation of mitochondrial reactive oxygen species. FASEB J. 21, 1099–1106. doi: 10.1096/fj.06-6644com
Pubmed Abstract | Pubmed Full Text | CrossRef Full Text | Google Scholar
Keywords: heme, heme oxygenase, bioenergetics, hemoprotein, CO-RM
Citation: Schallner N and Otterbein LE (2015) Friend or foe? Carbon monoxide and the mitochondria. Front. Physiol. 6:17. doi: 10.3389/fphys.2015.00017
Received: 24 November 2014; Paper pending published: 03 December 2014;
Accepted: 11 January 2015; Published online: 03 February 2015.
Edited by:
Pamela Boon Li Pun, Defence Medical and Environmental Research Institute, SingaporeReviewed by:
Nazareno Paolocci, Johns Hopkins University, USAGregory M. Vercellotti, University of Minnesota, USA
Copyright © 2015 Schallner and Otterbein. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: lotterbe@bidmc.harvard.edu