CO-mediated cytoprotection is dependent on cell metabolism modulation

This work was supported by Fundação para a Ciência e Tecnologia (FCT) grant UID/Multi/04462/2013, I&D 2015–2020 iNOVA4Health - Programme in Translacional Medicine. FCT provided individual financial support to CFP (SFRH/BD/106057/2015), DDP (PD/BD/128338/2017), NLS (PD/BD/127819/2016) and HLAV (IF/00185/2012).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.publishersversionpublishe