Uncouplers of oxidative phosphorylation !

Uncouplers let protons cross the inner membrane without ATP synthase: more fuel is burned, temperature rises and ATP falls.

Updated 2026-11-01

Key facts

Uncoupling separates electron transport from ATP synthesis: O₂ is consumed, but the energy leaves as heat.
2,4-Dinitrophenol (DNP) is a lipid-soluble weak acid that carries H⁺ back into the matrix.
Physiological uncoupler: UCP1 (thermogenin) in brown fat.
Others: toxic doses of salicylates, some pesticides and excess thyroid hormone (more proton leak and higher basal expenditure).

The chain keeps pumping protons into the intermembrane space.
The uncoupler returns them to the matrix by a shortcut, bypassing ATP synthase.
The gradient falls and the respiratory-control brake disappears: the chain runs faster and burns more O₂, NADH and fat.
The gradient's energy is released as heat: fever and hyperthermia.
With less ATP, the cell speeds up glycolysis and makes lactate.

DNP was sold for weight loss in the 1930s and still circulates illegally: it causes severe hyperthermia, rigidity and death.
Severe salicylate poisoning combines uncoupling, hyperthermia and high anion gap metabolic acidosis.
Malignant hyperthermia is not mitochondrial uncoupling: it is uncontrolled Ca²⁺ release in muscle, although it also produces heat.

Think of the answer, then tap the question to see it.

What does 2,4-dinitrophenol do to O₂ consumption and ATP synthesis?

It raises O₂ consumption and lowers ATP synthesis: it carries H⁺ into the matrix without ATP synthase and the energy leaves as heat.

What is the newborn's physiological uncoupler?

UCP1 (thermogenin) in brown fat.

Why does salicylate poisoning cause fever?

At toxic doses it uncouples oxidative phosphorylation: the gradient's energy is released as heat.

Educational information, not medical advice. For any symptom, see a health professional.

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Representative model, for educational purposes only.