Extremely low concentrations of cyanide stimulate cell growth, hinting that the chemical’s bad rap is only part of the story

May 20, 2021

Low levels of cyanide may actually be beneficial to human cells. (Shutterstock)

Despite its infamous reputation as a poison, environmental contaminant and weapon in chemical warfare, cyanide may have some beneficial physiological effects at extremely low concentrations, new research indicates.

Scientists who exposed human cell cultures to tiny doses of the chemical found that cell growth picked up modestly. The results indicate that cyanide may be a previously unrecognized kind of gaseous messenger molecule in mammalian cells, the researchers reported May 10 in Proceedings of the National Academy of Sciences

"At low concentrations it's something totally different than at high concentrations," said Csaba Szabo, a professor in the department of pharmacology at the University of Fribourg in Switzerland and last author of the study. "Maybe this is another gas that has some regulatory role at the low end of the curve, and then the toxicity at the high end of the curve."

The researchers only looked at cell cultures, so it still remains to be seen how well the findings represent cyanide's behavior in living animals, Szabo says.

Cyanide is a fast-acting poison that causes symptoms ranging from headaches and vomiting to convulsions, respiratory failure and death. At the same time, cyanide is known to play important physiological roles in plants and bacteria, Szabo says. Many plants use cyanide for self-defense; a toxin that breaks down into cyanide is found in peach pits and numerous other fruit stones and seeds. Scientists have also previously detected several cyanide-producing enzymes in mammalian cells.

There are several gases produced in very small amounts in humans and other organisms that carry signals relating to various physiological processes by diffusing from one cell to another. These include nitric oxide, carbon monoxide and hydrogen sulfide. Szabo and his team suspected that cyanide might behave as a fourth kind of gaseous messenger. 

The researchers examined how quickly several types of human cells from the liver, immune system and intestine replicated with and without cyanide. Cells that were exposed to very, very low doses of cyanide — many thousands of times less than the concentration that begins to cause cell death — grew about 10% to 20% faster than ones that hadn't encountered cyanide. As the concentration of cyanide increased, the rate of cell growth slowed and eventually cells began to die, Szabo says.

The reason for this effect is that cyanide, like the three other known gaseous messengers, targets the cell's energy-producing machinery, or mitochondria; if a cell has more energy, it can divide and make more copies at a faster rate. 

Szabo and his team also observed that cells exposed to low concentrations of cyanide consumed more oxygen and produced more of the vital energy-carrying molecule adenosine triphosphate — signs that the cells were busy making energy. By contrast, higher concentrations of cyanide reduced oxygen consumption and adenosine triphosphate production. 

The researchers additionally confirmed the presence in human liver cells of six enzymes known to produce or break down cyanide. 

In another experiment, the team examined how cells reacted to compounds secreted by the bacterium Pseudomonas aeruginosa, which produces cyanide and often causes damaging lung infections in people with cystic fibrosis. The researchers found that very diluted samples stimulated the metabolism of the cells, while more concentrated samples suppressed it. When they repeated the experiment with a mutant strain of Pseudomonas lacking its cyanide-producing enzyme, both of these effects were absent. 

At high concentrations, cyanide prevents cells from using oxygen and shuts down the production of adenosine triphosphate. But at low doses, the chemical removes the molecular "brakes" on this process, Szabo says.

"It's like a car which is electronically controlled for speed; it doesn't let you go as fast as the car could go," he said. At low concentrations, cyanide "takes away the thing that doesn't let it go at maximal speed."

He suspects that the influence of cyanide and the other three gaseous messengers is related to the origin of mitochondria, which are thought to have started out as an independent microbe that was engulfed by another cell billions of years ago. Back then, there was little oxygen in the atmosphere — but cyanide and the other gases were present in the air, and the bacteria would have been adapted to use them, Szabo says.

"The most important takeaway from this research is that hydrogen cyanide, one of the most infamous poisons in mammalian cells, which leads to tissue hypoxia and death by inhibiting mitochondrial respiration at high concentrations, at lower concentrations may stimulate mitochondrial metabolism and improve bioenergetics," said Pal Pacher, a senior investigator at the Laboratory of Cardiovascular Physiology and Tissue Injury at the National Institute on Alcohol Abuse and Alcoholism, who wrote a commentary to accompany the new study that will be published in PNAS.

The work raises numerous questions about what roles cyanide might play in the body. In the future, Szabo and his colleagues hope to investigate how cyanide production is controlled in cells, how this might be altered in different diseases and whether it could have any therapeutic uses.

"This is just the first step," Szabo said, adding that probing cyanide's mysteries "is going to keep us entertained for many, many years."

The study, "Physiological concentrations of cyanide stimulate mitochondrial Complex IV and enhance cellular bioenergetics," published May 10 in PNAS, was authored by Elisa B. Randi, Karim Zuhra, Laszlo Pecze, Theodora Panagaki and Csaba Szabo, University of Fribourg.

This story has been updated to include comment from Pal Pacher.

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