CO-mediated cytoprotection is dependent on cell metabolism modulation

Abstract

Carbon monoxide (CO) is a gasotransmitter endogenously produced by the activity of heme oxygenase, which is a stress-response enzyme. Endogenous CO or low concentrations of exogenous CO have been described to present several cytoprotective functions: anti-apoptosis, anti-inflammatory, vasomodulation, maintenance of homeostasis, stimulation of preconditioning and modulation of cell differentiation. The present review revises and discuss how CO regulates cell metabolism and how it is involved in the distinct cytoprotective roles of CO. The first found metabolic effect of CO was its increase on cellular ATP production, and since then much data have been generated. Mitochondria are the most described and studied cellular targets of CO. Mitochondria exposure to this gasotransmitter leads several consequences: ROS generation, stimulation of mitochondrial biogenesis, increased oxidative phosphorylation or mild uncoupling effect. Likewise, CO negatively regulates glycolysis and improves pentose phosphate pathway. More recently, CO has also been disclosed as a regulating molecule for metabolic diseases, such as obesity and diabetes with promising results.

Keywords: Carbon monoxide; Glycolysis; Metabolism; Mitochondrial biogenesis; Oxidative phosphorylation; Pentose phosphate pathway; ROS signaling.

Fig. 1

CO promotes mitochondrial ROS generation. CO can bind and inhibit cytochrome c oxidase, which accumulates electrons at the mitochondrial electron transport chain. Accumulation of electrons enhances the probability of O₂ reduction into anion superoxide, which is quickly converted into other ROS, namely hydrogen peroxide. Because low amounts of CO partially and transitorily binds to cytochrome c oxidase low levels of ROS are generated that act as cell signaling molecules.

Fig. 2

CO stimulates mitochondrial biogenesis. CO exposure upregulates the expression of peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α) and the nuclear respiratory factor-1 and 2 (Nrf-1/2), which regulate the expression of nuclear encoding mitochondrial proteins. PGC-1α interaction with Nrf-1/2 also coordinates the upregulation of the mitochondrial transcription factor (TFAM) that modulates transcription of mitochondrial DNA. These factors are all involved in CO-induced mitochondrial biogenesis.

Fig. 3

Main cellular metabolic pathways modulated by CO: mitochondrial metabolism, glycolysis and pentose phosphate pathway. Low levels of CO enhance TCA, improve mitochondrial OXPHOS, increase oxygen consumption and production of ATP. Accordingly, in most of the tested models (cell type and pathophysiological conditions) CO decreases glycolysis. Finally CO modulates redox processes: ROS appear as signaling molecules for CO mode of action and one of the cytoprotective properties of CO is anti-oxidant. Thus it is not surprising that CO also stimulates PPP, a critical pathway responsible to maintaining the reducing capacity of the cell, as well as the cellular nucleotides pool.

Fig. 4

CO promotes mild uncoupling effect in mitochondria. CO-induced mild uncoupling is dependent on ANT and UCP and this event is associated with anti-inflammatory role of CO. It is speculated that a small leakage of protons into mitochondrial matrix may generate ROS and accelerate respiratory chain for maintaining mitochondrial membrane potential, both events shall improve mitochondrial function and metabolism.