Carbon monoxide signalsviainhibition of cytochromecoxidase and generation of mitochondrial reactive oxygen species

Abstract

Carbon monoxide (CO), which is produced endogenously in the breakdown of heme, has been recognized as an important physiological second messenger similar to NO. Additionally, pharmacological delivery of CO is protective in numerous models of injury, including ischemia/reperfusion, transplantation, hemorrhagic shock, and endotoxemia. However, the mechanism of action of CO is only partially elucidated focused primarily on how it modulates the cellular response to stress. The purpose of these investigations is to test the hypothesis that CO acts via inhibition of cytochrome c oxidase leading to the generation of low levels of reactive oxygen species (ROS) that in turn mediate subsequent adaptive signaling. We show here that CO increases ROS generation in RAW 264.7 cells, which is inhibited by antimycin A and is absent in respiration-deficient rho0 cells. CO inhibits cytochrome c oxidase, while maintaining cellular ATP levels and increasing mitochondrial membrane potential. The addition of antioxidants or inhibition of complex III of the electron transport chain by antimycin A attenuates the inhibitory effects of CO on lipopolysaccharide (LPS)-induced TNF-alpha and blocked CO-induced p38 MAPK phosphorylation, which we previously have shown to be important in the anti-inflammatory effects of CO.

A carbon monoxide-releasing molecule (CORM-3) uncouples mitochondrial respiration and modulates the production of reactive oxygen species

“…7A). This result confirms that CO, via inhibition of complex IV, is able to promote electron leakage and ROS production at the level of complex III [31]. In a second experiment we tested the effect of CORM-3 on H 2 .…”

“…This demonstrates the specific effect of CORM-3 in reducing complex I-derived ROS. Recent data reveal that both CO-RMs and CO gas in different cell types promote a transient and subtle increase in mitochondrial ROS production [31,49,50], a signaling process that might well justify the emerging cardioprotective properties of CO. In fact, CO and CO-RMs effectively mitigate myocardial ischemia-reperfusion injury, cardiac allograft rejection, cardiomyopathy and heart failure through mechanisms that appear to involve the preservation of mitochondrial function, bioenergetics and cardiac metabolism [10,13,14,51].…”

“…Because CO has been shown to favor the generation of reactive oxygen species (ROS) from mitochondria [31] and mild uncoupling is assumed to prevent mitochondrial ROS formation [32], we next studied the effect of CORM-3 on the rate of ROS produced under different respiratory conditions. Mitochondrial ROS can be produced by the ETC through electron leak at complexes I and III [19].…”

The effects of chronic carbon monoxide treatment on diet-induced obesity and Rev-erb-alpha target gene expression in adipose tissue

“…It is difficult to reconcile the differences between our findings and that of Hosick et al [8,9]. Since some of the beneficial effects of CO are mediated by an increase in reactive oxygen species [25], this response may be abrogated in mice with established weight stable obesity because of the already high levels of ROS [26]. Finally, the lack of a CO effect in the present study and that of Hosick et al [9] may be related to the delivery of the gas by inhalation rather than via CO releasing molecules [8], particularly since CO gas is primarily transported bound to hemoglobin and CO releasing molecules reach tissues independent of hemoglobin.…”

Redox Signaling Pathways Involved in Neuronal Ischemic Preconditioning

“…CO has also been demonstrated to generate low levels of mitochondrial ROS formation under normal physiological oxygen levels [100,101]. In highly metabolically active tissues, such as the brain and heart, CO has been demonstrated to bind to cytochrome oxidase which produces reduction responses in cytochrome bc1 portion of the electron transport chain, as well as, ROS generation [102].…”