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<p>Small, gaseous molecules such as nitric oxide, carbon monoxide and hydrogen sulfide are produced as signalling molecules in mammalian cells. Here, we show that low concentrations of cyanide are generated endogenously in various mammalian tissues and cells. We detect cyanide in several cellular compartments of human cells and in various tissues and the blood of mice. Cyanide production is stimulated by glycine, occurs at the low pH of lysosomes and requires peroxidase activity. When generated at a specific rate, cyanide exerts stimulatory effects on mitochondrial bioenergetics, cell metabolism and cell proliferation, but impairs cellular bioenergetics at high concentrations. Cyanide can modify cysteine residues via protein <i>S</i>-cyanylation, which is detectable basally in cells and mice, and increases in response to glycine. Low-dose cyanide supplementation exhibits cytoprotective effects in hypoxia and reoxygenation models in vitro and in vivo. Conversely, pathologically elevated cyanide production in nonketotic hyperglycinaemia is detrimental to cells. Our findings indicate that cyanide should be considered part of the same group of endogenous mammalian regulatory gasotransmitters as nitric oxide, carbon monoxide and hydrogen sulfide.</p>

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Regulation of mammalian cellular metabolism by endogenous cyanide production

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月3日

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  • Karim Zuhra,
  • Maria Petrosino,
  • Lucia Janickova,
  • Jovan Petric,
  • Kelly Ascenção,
  • Thibaut Vignane,
  • Moustafa Khalaf,
  • Thilo M. Philipp,
  • Stella Ravani,
  • Abhishek Anand,
  • Vanessa Martins,
  • Sidneia Santos,
  • Serkan Erdemir,
  • Sait Malkondu,
  • Barbara Sitek,
  • Taha Kelestemur,
  • Anna Kieronska-Rudek,
  • Tomas Majtan,
  • Luis Filgueira,
  • Darko Maric,
  • Stefan Chlopicki,
  • David Hoogewijs,
  • György Haskó,
  • Andreas Papapetropoulos,
  • Brian A. Logue,
  • Gerry R. Boss,
  • Milos R. Filipovic,
  • Csaba Szabo

摘要

Small, gaseous molecules such as nitric oxide, carbon monoxide and hydrogen sulfide are produced as signalling molecules in mammalian cells. Here, we show that low concentrations of cyanide are generated endogenously in various mammalian tissues and cells. We detect cyanide in several cellular compartments of human cells and in various tissues and the blood of mice. Cyanide production is stimulated by glycine, occurs at the low pH of lysosomes and requires peroxidase activity. When generated at a specific rate, cyanide exerts stimulatory effects on mitochondrial bioenergetics, cell metabolism and cell proliferation, but impairs cellular bioenergetics at high concentrations. Cyanide can modify cysteine residues via protein S-cyanylation, which is detectable basally in cells and mice, and increases in response to glycine. Low-dose cyanide supplementation exhibits cytoprotective effects in hypoxia and reoxygenation models in vitro and in vivo. Conversely, pathologically elevated cyanide production in nonketotic hyperglycinaemia is detrimental to cells. Our findings indicate that cyanide should be considered part of the same group of endogenous mammalian regulatory gasotransmitters as nitric oxide, carbon monoxide and hydrogen sulfide.