Mitochondria and carbon monoxide: cytoprotection and control of cell metabolism – a role for Ca²⁺?

<jats:title>Abstract</jats:title><jats:p>Carbon monoxide (CO) is an endogenously produced gasotransmitter with important biological functions: anti‐inflammation, anti‐apoptosis, vasomodulation and cell metabolism modulation. The most recognized cellular target for CO is the mitochondria. Physiological concentrations of CO generate mitochondrial reactive oxygen species (ROS), which are signalling molecules for CO‐induced pathways. Indeed, small amounts of ROS promote cytoprotection by a preconditioning effect. Furthermore, CO prevents cell death by limiting mitochondrial membrane permeabilization, which inhibits the release of pro‐apoptotic factors into the cytosol; both events are ROS dependent. CO also increases the ability of mitochondria to take up Ca<jats:sup>2+</jats:sup>. Mitochondrial metabolism is modulated by CO, namely by increasing TCA cycle rate, oxidative phosphorylation and mitochondrial biogenesis, which, in turn, increases ATP production. CO's modulation of metabolism might be important for cellular response to diseases, namely cancer and ischaemic diseases. Finally, another cytoprotective role of CO involves the control of Ca<jats:sup>2+</jats:sup> channels. By limiting the activity of T‐type and L‐type Ca<jats:sup>2+</jats:sup> channels, CO prevents excitotoxicity‐induced cell death and modulates cell proliferation. Several questions concerning Ca<jats:sup>2+</jats:sup> signalling, mitochondria and CO can be asked, for instance whether CO modulation of cell metabolism would be dependent on the mitochondrial Ca<jats:sup>2+</jats:sup> uptake capacity, since small amounts of Ca<jats:sup>2+</jats:sup> can increase mitochondrial metabolism. Whether CO controls Ca<jats:sup>2+</jats:sup> communication between mitochondria and endoplasmic reticulum is another open field of research. In summary, CO emerges as a key gasotransmitter in the control of several cellular functions of mitochondria: metabolism, cell death and Ca<jats:sup>2+</jats:sup> signalling. <jats:boxed-text content-type="graphic" position="anchor"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" mimetype="image/png" position="anchor" specific-use="enlarged-web-image" xlink:href="graphic/tjp6858-gra-0001-m.png"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text></jats:p>