Carbon monoxide – beyond toxicity?

Abstract

Carbon monoxide (CO) intoxication is one of the most frequent causes of accidental poisoning, mechanistically related to the inhibition of oxygen transport following blockage of the oxygen binding site of hemoglobin. However, it has become evident that CO is also a gaseous signaling molecule like nitric oxide and capable to trigger cellular stress responses in complex organisms. Endogenously, CO is synthesized upon degradation of heme by heme oxygenases (HOs) of which two enzymatically active isoenzymes are known in mammals; the stress-inducible HO-1 and the constitutively expressed HO-2. Among other pathways, HO-1 expression is stimulated by the Nrf2/Keap1 system which senses electrophilic compounds including alkylating agents and reactive oxygen species (ROS) such as superoxide or hydrogen peroxide. In context with ROS, HO-1 expression has been associated with antioxidant defense related to the heme-metabolite redox pair biliverdin/bilirubin. Studies on CO signaling were facilitated by the introduction of so called “CO releasing molecules” (CORMs), which allow for the controlled release of the compound in biological systems. Obviously, major biological targets of CO comprise intracellular heme-proteins such as cytochrome c oxidase of the respiratory chain, cytochrome P450-dependent monooxygenases (CYPs), or NADPH oxidases. From toxicological studies it is known that exposure to high amounts of CO provokes an inhibition of mitochondrial respiration and increased generation of ROS. In contrast, biological response to low amounts of CO comprises moderate mitochondrial uncoupling (proton leakage) due to the activation of channels including phosphate carrier (PiC), adenine nucleotide translocase (ANT) or large-conductance Ca2+-activated K+ channels (BKCa). Uncoupling of mitochondrial respiration from ATP production is accompanied by a loss of mitochondrial membrane potential – a key sensor and regulator of mitochondrial quality control and mitophagy. Inhibitory effects of CO on mitochondrial respiration are compensated by an increased glycolysis. However, on a short term, utilization of glucose is shifted to the pentose phosphate pathway, to provide NADPH for detoxification. It is notable that endogenous CO production is associated with the physiological response against exogenous electrophilic insult like Nrf2-dependent expression of phase II enzymes or glutathione synthesis. In contrast phase I enzymes such as CYPs which usually generate more electrophiles are inhibited by CO. Together with direct and indirect transient effects on energy metabolism and mitochondrial quality control CO may be an important regulator in cellular stress response.