How does cyanide enter the mitochondrial matrix?

From the Guidelines

Cyanide enters the mitochondrial matrix primarily through passive diffusion across the mitochondrial membrane, allowing it to exert its toxic effects by binding to cytochrome c oxidase and blocking cellular respiration. This process occurs because cyanide, in its hydrogen cyanide (HCN) form, is a small, uncharged molecule that can easily penetrate the lipid bilayers of both the outer and inner mitochondrial membranes without requiring specific transport proteins 1. Once inside the matrix, cyanide binds to the iron atom in the heme a3 group of cytochrome c oxidase (Complex IV) in the electron transport chain, effectively blocking the enzyme's ability to transfer electrons to oxygen. This inhibition of cytochrome c oxidase prevents cells from using oxygen for ATP production through oxidative phosphorylation, resulting in cellular hypoxia despite normal oxygen levels in the blood. Key aspects of cyanide toxicity include:

• Rapid onset of symptoms due to the cessation of aerobic cell metabolism
• Binding to cytochrome c oxidase, stopping cellular respiration and adenosine triphosphate production
• Potential sources of exposure including smoke inhalation, industrial exposures, self-poisoning, terrorism, or the administration of sodium nitroprusside
• Importance of immediate antidotes like hydroxocobalamin and nitrites to counteract the effects of cyanide poisoning, as noted in recent guidelines 1. The mechanism of cyanide toxicity highlights the critical need for prompt treatment to prevent or mitigate the severe consequences of exposure, including arrhythmias, apnea, hypotension with bradycardia, seizures, and cardiovascular collapse.

From the FDA Drug Label

Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria

Cyanide gets to the mitochondrial matrix by binding rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. This binding prevents the cell from using oxygen and forces anaerobic metabolism. 2

From the Research

Mechanism of Cyanide Transport to Mitochondrial Matrix

• The exact mechanism of cyanide transport to the mitochondrial matrix is not explicitly described in the provided studies 3, 4, 5, 6, 7.
• However, it is known that cyanide inhibits cytochrome c oxidase, the terminal oxidase of the mitochondrial respiratory pathway, leading to the inhibition of cell oxygen utilization and resulting in histotoxic anoxia 3.
• The studies focus on the effects of cyanide on cytochrome c oxidase activity and the efficacy of various prophylactics and antidotes, such as sulfur donors, sodium nitrite, and hydroxocobalamin, in preventing or treating cyanide poisoning 3, 4, 5, 6, 7.
• The interaction of cyanide with cytochrome c oxidase and the role of nitric oxide in enhancing cyanide inhibition are discussed in some studies 5.
• However, the specific details of how cyanide reaches the mitochondrial matrix are not provided in the available evidence.

Related Findings

• The studies suggest that cyanide can rapidly react and cause arrest of aerobic metabolism, leading to severe symptoms and requiring quick treatment with a cyanide antidote 4, 7.
• The use of combination therapies, such as hydroxocobalamin and sodium thiosulfate, may have a positive effect on survival and prevent long-term neurological and visual sequelae in cases of massive cyanide poisonings 7.
• The antidotal action of sodium nitrite is partly explained by the generation of high mitochondrial levels of nitric oxide, which antagonizes the cytochrome c oxidase inhibition 5.