2. Academic Validation
  3. Regulation of mammalian cellular metabolism by endogenous cyanide production

Regulation of mammalian cellular metabolism by endogenous cyanide production

  • Nat Metab. 2025 Mar;7(3):531-555. doi: 10.1038/s42255-025-01225-w.
Karim Zuhra # 1,  Maria Petrosino # 1,  Lucia Janickova 1,  Jovan Petric 2,  Kelly Ascenção 1,  Thibaut Vignane 2,  Moustafa Khalaf 3,  Thilo M Philipp 1,  Stella Ravani 4,  Abhishek Anand 1,  Vanessa Martins 1,  Sidneia Santos 1,  Serkan Erdemir 5,  Sait Malkondu 6,  Barbara Sitek 7,  Taha Kelestemur 8,  Anna Kieronska-Rudek 1 7,  Tomas Majtan 1,  Luis Filgueira 9,  Darko Maric 10,  Stefan Chlopicki 7,  David Hoogewijs 10,  György Haskó 8,  Andreas Papapetropoulos 4 11,  Brian A Logue 3,  Gerry R Boss 12,  Milos R Filipovic 13 14,  Csaba Szabo 15
Affiliations

Affiliations

  • 1 Section of Pharmacology, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
  • 2 Leibniz Institute for Analytical Sciences, Dortmund, Germany.
  • 3 Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD, USA.
  • 4 Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
  • 5 Selcuk University, Science Faculty, Department of Chemistry, Konya, Turkey.
  • 6 Giresun University, Faculty of Engineering, Department of Environmental Engineering, Giresun, Turkey.
  • 7 Jagiellonian Centre for Experimental Therapeutics, Jagiellonian University, Krakow, Poland.
  • 8 Department of Anesthesiology, Columbia University, New York, NY, USA.
  • 9 Section of Anatomy, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
  • 10 Department of Endocrinology, Metabolism and Cardiovascular System, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
  • 11 Laboratory of Pharmacology, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece.
  • 12 Department of Medicine, University of California, San Diego, San Diego, CA, USA.
  • 13 Leibniz Institute for Analytical Sciences, Dortmund, Germany. milos.filipovic@glasgow.ac.uk.
  • 14 School of Molecular Biosciences, University of Glasgow, Glasgow, UK. milos.filipovic@glasgow.ac.uk.
  • 15 Section of Pharmacology, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland. csaba.szabo@unifr.ch.
  • # Contributed equally.
PMID: 40033006 DOI: 10.1038/s42255-025-01225-w
Abstract

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.

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