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

Proc Natl Acad Sci U S A. 2021 May 18;118(20):e2026245118. doi: 10.1073/pnas.2026245118.


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.

Keywords: bioenergetics; gasotransmitters; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyanides / metabolism
  • Cyanides / pharmacology*
  • Electron Transport Complex IV / drug effects*
  • Electron Transport Complex IV / physiology
  • Energy Metabolism / drug effects*
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Mitochondria / drug effects*
  • Mitochondria / metabolism


  • Cyanides
  • Electron Transport Complex IV