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.

在哺乳动物细胞中，氰化物被视为一种细胞毒剂，它通过抑制线粒体复合物 IV（细胞色素 C 氧化酶 [CCOx]）发挥作用。然而，目前的报告表明，氰化物对 CCOx 的影响是双相的；低（纳摩尔至低微摩尔）浓度会刺激 CCOx 活性，而较高（高微摩尔）浓度会产生“经典”抑制作用。低浓度的氰化物刺激线粒体电子传递和细胞内三磷酸腺苷 (ATP) 升高，从而刺激细胞增殖。氰化物对 CCOx 的刺激作用与去除其催化 30-和 57-kDa 亚基上的组成性、抑制性谷胱甘肽化有关。转移稀释的铜绿假单胞菌（一种产生氰化物的细菌）哺乳动物细胞的上清液刺激了细胞生物能学，而浓缩的上清液则具有抑制作用。来自缺乏产生氰化物的酶的突变假单胞菌的上清液不存在这些影响。这些结果提出了一种可能性，即低内源水平的氰化物在哺乳动物中起到调节作用。事实上，在 HepG2 细胞中证实了六种推定的哺乳动物氰化物产生和/或代谢酶的表达；其中之一（髓过氧化物酶）在氰化物暴露后表现出双相调节。氰化物与“经典”哺乳动物气体传递体 NO、CO 和 H ₂ S 具有相同的特征，可被认为是第四种哺乳动物气体传递体。