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[Biochemistry](https://durgical.com/en/biochemistry/) · Topic

# 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).

## In detail

- 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.

**Also called**
2,4-Dinitrophenol, Thermogenesis

## Clinical notes

- 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.

## Pathways

- [Electron transport chain and oxidative phosphorylation](https://durgical.com/en/biochemistry/pathways/electron-transport-chain-and-oxidative-phosphorylation/)

## Related conditions

- [Obesity](https://durgical.com/en/conditions/obesity/)

## Related

- [UCP1 (thermogenin)](https://durgical.com/en/biochemistry/enzymes/ucp1/)
- [Chemiosmosis and the proton gradient](https://durgical.com/en/biochemistry/topics/chemiosmosis-and-the-proton-gradient/)
- [ATP synthase (complex V)](https://durgical.com/en/biochemistry/enzymes/atp-synthase/)

## Test yourself

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.

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

Sources: [Mitochondrial Uncoupling](https://reactome.org/PathwayBrowser/#/R-HSA-166187) (Reactome, 2026); [2,4-Dinitrophenol (CID 1493)](https://pubchem.ncbi.nlm.nih.gov/compound/1493) (PubChem, NCBI, 2026) · Public domain; [8J1N: Structure of human UCP1 in the DNP-bound state](https://www.rcsb.org/structure/8J1N) (RCSB Protein Data Bank, 2026).

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Representative model, for educational purposes only.

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License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/topics/uncouplers-of-oxidative-phosphorylation/