Physiological concentrations of cyanide stimulate mitochondrial Complex IV and enhance cellular bioenergetics

Abstract

In mammalian cells, cyanide is viewed as a cytotoxic agent, which exerts its effects through inhibition of mitochondrial Complex IV (Cytochrome C oxidase [CCOx]). However, the current report demonstrates that cyanide’s effect on CCOx is biphasic; low (nanomolar to low-micromolar) concentrations stimulate CCOx activity, while higher (high-micromolar) concentrations produce the “classic” inhibitory effect. Low concentrations of cyanide stimulated mitochondrial electron transport and elevated intracellular adenosine triphosphate (ATP), resulting in the stimulation of cell proliferation. The stimulatory effect of cyanide on CCOx was associated with the removal of the constitutive, inhibitory glutathionylation on its catalytic 30- and 57-kDa subunits. Transfer of diluted Pseudomonas aeruginosa (a cyanide-producing bacterium) supernatants to mammalian cells stimulated cellular bioenergetics, while concentrated supernatants were inhibitory. These effects were absent with supernatants from mutant Pseudomonas lacking its cyanide-producing enzyme. These results raise the possibility that cyanide at low, endogenous levels serves regulatory purposes in mammals. Indeed, the expression of six putative mammalian cyanide-producing and/or -metabolizing enzymes was confirmed in HepG2 cells; one of them (myeloperoxidase) showed a biphasic regulation after cyanide exposure. Cyanide shares features with “classical” mammalian gasotransmitters NO, CO, and H2S and may be considered the fourth mammalian gasotransmitter.

Biological hydrogen cyanide emission globally impacts the physiology of both HCN-emitting and HCN-perceivingPseudomonas

“…Not unlike phenazines, which were also first categorized as “mere secondary metabolites” and which later turned out to act as internal signalling molecules with diverse and important cellular functions 28 , we show here that HCN is much more than a respiratory toxin, and acts as an inter- and extracellular signal on both producing and receiving cells. These findings are in line with recent reports on the ability of HCN to induce broad physiological effects in both plant and human cells 29,30 . Compared with phenazines, HCN is a volatile molecule and as such, its zone of influence is expected to be much broader 1 .…”

The two faces of cyanide: an environmental toxin and a potential novel mammalian gasotransmitter

“…Similarly, S‐glutathionylation, a post‐translational modification involved in modulation of energy metabolism and oxidative damage prevention, has been observed in different mitochondrial complexes, including CCOx [ 27 , 28 ]. As shown working on HepG2 cells and isolated enzyme from bovine heart, we have reported that S‐glutathionylation induces a downregulation of CCOx activity, and interestingly, this post‐translational modification could be reversed by nanomolar concentrations of cyanide [ 29 ]. As discussed below, CCOx is also targeted by NO which is responsible for partial inhibition of its enzymatic activity and maintaining ΔΨ m levels under control [ 30 ].…”

“…A subsequent study comparing the binding parameters of cyanide to different states of CCOx, estimated that the partially reduced enzyme, populated during turnover, displays a binding affinity to cyanide that is 5 orders of magnitude higher as compared to the fully oxidized enzyme [ 34 ]. As shown by sequential mixing and rapid scan stopped flow spectroscopy, a one‐electron reduction of a 3 /Cu B is sufficient to induce a rapid cyanide binding [ 29 ]. According to this model, the very first binding site is Cu B and two possible mechanisms are conceivable.…”

Impact of Hydrogen Sulfide on Mitochondrial and Bacterial Bioenergetics

“…However, it was discovered that in mammals H 2 S has physiological relevance and is endogenously generated [ 1 , 2 ]. Currently, H 2 S is considered to be a member of the class of gasotransmitters or, in other words, endogenous gaseous signaling molecules, along with nitric oxide and carbon monoxide [ 3 , 4 , 5 , 6 , 7 ]. Although still debated, cyanide has also recently been proposed to be part of this class [ 7 , 8 ].…”

“…Currently, H 2 S is considered to be a member of the class of gasotransmitters or, in other words, endogenous gaseous signaling molecules, along with nitric oxide and carbon monoxide [ 3 , 4 , 5 , 6 , 7 ]. Although still debated, cyanide has also recently been proposed to be part of this class [ 7 , 8 ]. H 2 S contributes to the regulation of important physiological processes in the cardiovascular, gastrointestinal, nervous, and respiratory systems.…”