A toxicologist suspects cyanide poisoning in a patient found unresponsive. Labs show arterial-venous O2 difference is nearly zero despite high arterial pO2, and there is severe lactic acidosis. Which specific step in the ETC is inhibited by cyanide?

• A Complex I (NADH-CoQ reductase) — cyanide binds FMN at the NADH oxidation site
• B Complex IV (cytochrome c oxidase) — cyanide binds the ferric (Fe3+) form of heme a3, blocking electron transfer to O2 ✓
• C Complex III (cytochrome bc1) — cyanide inhibits cytochrome b, blocking Q-cycle
• D ATP synthase (Complex V) — cyanide blocks the F0 proton channel

Explanation

Cyanide (CN-) and azide (N3-) are classic inhibitors of Complex IV (cytochrome c oxidase, COX), binding to the Fe3+ (ferric) heme a3 center and preventing O2 reduction to water. This stops electron flow through the entire ETC (all NADH and FADH2 regeneration halts), abolishing oxidative phosphorylation. Cells switch entirely to anaerobic glycolysis → lactic acidosis. Venous blood retains high O2 saturation (tissues cannot use O2), making mixed venous PO2 nearly equal to arterial PO2 — the key physical sign. Treatment: hydroxocobalamin (Co3+ binds CN-) or nitrites (convert Hb to metHb which has higher CN- affinity).

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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Written and medically reviewed by the StethoPrep medical team.