Which of the following compounds acts as an uncoupler of oxidative phosphorylation by dissipating the proton gradient across the inner mitochondrial membrane?

Explanation

## Mechanism of Uncoupling **Key Point:** DNP is a lipophilic weak acid that shuttles protons across the inner mitochondrial membrane, bypassing ATP synthase and dissipating the proton gradient as heat rather than coupling it to ATP synthesis. ## How DNP Works 1. DNP is protonated in the intermembrane space (lower pH) 2. Crosses the lipid bilayer in its neutral form 3. Releases the proton in the matrix (higher pH) 4. Returns to the intermembrane space in its deprotonated form 5. Cycle repeats, dissipating energy as heat ## Comparison of Mitochondrial Poisons | Agent | Mechanism | Effect on O₂ Consumption | Effect on ATP | Category | |-------|-----------|-------------------------|---------------|----------| | **DNP** | Proton shuttle (uncoupler) | **Increases** | Decreases | Uncoupler | | Cyanide | Blocks Complex IV | Decreases | Decreases | Inhibitor | | Rotenone | Blocks Complex I | Decreases | Decreases | Inhibitor | | Carbon monoxide | Blocks Complex IV | Decreases | Decreases | Inhibitor | **High-Yield:** The critical distinction is that uncouplers **increase** oxygen consumption while **decreasing** ATP production, whereas inhibitors **decrease** both. ## Clinical Pearl DNP was once used as a weight-loss drug but is now banned in most countries due to its narrow margin between therapeutic and toxic doses. It causes fatal hyperthermia because heat production cannot be controlled. **Mnemonic:** **U**ncouplers **I**ncrease O₂ uptake; **I**nhibitors **I**nhibit O₂ uptake.