Regulation of mammalian cellular metabolism by endogenous cyanide production.

Summary

This mechanistic study demonstrates that mammalian cells produce cyanide endogenously at low levels, where it functions as a gasotransmitter to enhance mitochondrial bioenergetics, metabolism, and proliferation, while higher concentrations are bioenergetically detrimental. Cyanide induces protein S-cyanylation and low-dose supplementation is cytoprotective in hypoxia/reoxygenation models; excessive production, as in nonketotic hyperglycinemia, is harmful.

Key Findings

• Endogenous cyanide was detected across cellular compartments in human cells and in mouse tissues/blood; production was stimulated by glycine, lysosomal low pH, and required peroxidase activity.
• At defined low generation rates, cyanide enhanced mitochondrial bioenergetics, cellular metabolism, and proliferation; high concentrations impaired bioenergetics.
• Cyanide induced protein S-cyanylation in cells and mice, which increased with glycine.
• Low-dose cyanide was cytoprotective in hypoxia/reoxygenation models; excessive production in nonketotic hyperglycinemia was detrimental.

Clinical Implications

While preclinical, these findings suggest potential biomarker and therapeutic avenues—modulating cyanide production/signaling or S-cyanylation—in ischemia-reperfusion injury and metabolic diseases; they also caution about disease states with pathological cyanide excess.

Limitations

• Translational applicability and therapeutic window in humans remain to be defined.
• Potential toxicity of cyanide necessitates careful dose-ranging and safety studies.

Future Directions

Define physiological ranges and kinetics of endogenous cyanide, map S-cyanylation targets, and test modulators (donors/inhibitors) and interactions with other gasotransmitters in metabolic and ischemic diseases.