Carbon Monoxide: A Pleiotropic Redox Regulator of Life and Death

Abstract

Despite recent technological progress, carbon monoxide poisoning is still one of the leading causes of domestic and industrial morbidity and mortality. The brain is particularly vulnerable to CO toxicity, and thus the majority of survivors develop delayed movement and cognitive complications. CO binds to haemoglobin in erythrocytes, preventing oxygen delivery to tissues, and additionally inhibits mitochondrial respiration. This renders the effect of CO to be closely related to hypoxia reperfusion injury. Oxygen deprivation, as well as CO poisoning and re-oxygenation, are shown to be able to activate the production of reactive oxygen species and to induce oxidative stress. Here, we review the role of reactive oxygen species production and oxidative stress in the mechanism of neuronal cell death induced by carbon monoxide and re-oxygenation. We discuss possible protective mechanisms used by brain cells with a specific focus on the inhibition of CO-induced ROS production and oxidative stress.

Keywords: CO toxicity; carbon monoxide poisoning; cell death; neuron; oxidative stress; reactive oxygen species.

Figure 1

The role of carbon monoxide in physiology and pathology. Left: at physiological conditions of the cell, CO is produced in the HO-1 and enables cell detoxification and signalling processes. Right: at pathologically acute high doses of CO-NOX, XO and mitochondria produce ROS with higher rates, which leads to lipid peroxidation and mPTP opening and, ultimately, to cell death. CO—carbon monoxide; ROS—reactive oxygen species; NOX—NADPH oxidases; HO-1—heme oxygenase; Nrf-2—nuclear factor erythroid 2-related factor 2; XO—xanthine oxidase; MAO—monoamine oxidase; NADPH—reduced nicotinamide adenine dinucleotide phosphate, NADP+—oxidised nicotinamide adenine dinucleotide phosphate; ATP—adenosine 3-phosphate; mPTP—mitochondrial permeability transition pore; MDA—malone dialdehyde; 8-OHdG-8-hydroxy-2′-deoxyguanosine; SOD—superoxide dismutase; CAT—catalase; GPx—glutathione peroxidase.