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

Abstract

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 Ca2+. 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 Ca2+ channels. By limiting the activity of T‐type and L‐type Ca2+ channels, CO prevents excitotoxicity‐induced cell death and modulates cell proliferation. Several questions concerning Ca2+ signalling, mitochondria and CO can be asked, for instance whether CO modulation of cell metabolism would be dependent on the mitochondrial Ca2+ uptake capacity, since small amounts of Ca2+ can increase mitochondrial metabolism. Whether CO controls Ca2+ 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 Ca2+ signalling.

Reactive oxygen species and antioxidant defense in human gastrointestinal diseases

“…HO-1 is upregulated mainly in macrophages and has two main effects. First, it increases the expression of c-kit (tyrosine kinase acting as a receptor for stem cell factor) and neuronal NOS, and second, it mediates carbon monoxide cytoprotection 107, 109…”

Exogenous carbon monoxide protects against mitochondrial DNA‑induced hippocampal pyroptosis in a model of hemorrhagic shock and resuscitation

“…carbon monoxide (cO), which is a type of neurotoxic molecule, has valuable cytoprotective effects, including positive and negative alterations of heme-containing enzymatic function and modulation of numerous cellular targets, such as extracellular signal-regulated kinase 1/2 (9). Exogenously administered cO affects cell metabolism and supports oxidative phosphorylation and mitochondrial respiration, enhancing ATP production and cellular energy status (10). carbon monoxide-releasing molecule (cORM)-3 has emerged as an excellent alternative to cO administration (11) and has been demonstrated to provide protection in inflammation and ischemia/reperfusion injury models by inhibiting the activation of nucleotide-binding oligomerization domain-like receptors pyrin domain-3 (NLRP3) inflammasome, which contains Exogenous carbon monoxide protects against mitochondrial DNA-induced hippocampal pyroptosis in a model of hemorrhagic shock and resuscitation NLRP3, apoptosis-associated speck-like protein containing a cARd domain (ASc) and pro-caspase-1, in sepsis and metabolic diseases (12,13).…”

Gaseous regulation of Ca2+ homeostasis; for better or worse?

“…At a physiological level there is still much to be learnt about these gases and their impact on cellular physiology. It does, however, seem clear that Ca 2+ homeostasis underpins an array of both H 2 S and CO cellular actions, as illustrated by Elies et al () and Oliveira et al () (Fig. ).…”

“…The underlying mechanisms by which CO benefits cellular physiology form an emerging research field and one that the Vieira group has contributed to (Oliveira et al . ). In this article Oliveira et al .…”

“…() highlight the influence of H 2 S on T‐type calcium channels, while Oliveira et al . () point to effects of CO on the mitochondria to influence calcium.…”