2,4-Dinitrophenol (DNP) acts as a chemical uncoupler of oxidative phosphorylation. The mechanism involves:

• A DNP inhibits ATP synthase by competing with phosphate at the Fo subunit
• B DNP inhibits Complex IV by binding cytochrome a3
• C DNP activates adenine nucleotide translocase, exporting ATP in exchange for ADP, depleting intramitochondrial ATP
• D DNP is a lipid-soluble weak acid that carries H+ ions across the inner mitochondrial membrane, dissipating the proton gradient as heat without ATP synthesis ✓

Explanation

DNP is a lipophilic weak acid (pKa ≈ 4.1) that can accept a proton at low pH (intermembrane space) and diffuse across the hydrophobic bilayer carrying H+, releasing it at higher pH (matrix), effectively short-circuiting the proton gradient. Electron transport continues (O2 is consumed and food is oxidised) but the energy is dissipated entirely as heat rather than driving ATP synthase. This is why DNP causes dangerous hyperthermia and weight loss. Physiological uncoupling via UCP-1 (thermogenin) in brown adipose tissue uses the same principle.

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

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Written and medically reviewed by the StethoPrep medical team.