Uncoupling protein 1 (UCP1) in brown adipose tissue dissipates the proton gradient without ATP synthesis. A synthetic chemical uncoupler like 2,4-dinitrophenol (DNP) was used as a weight-loss drug but caused fatal hyperthermia. The mechanism by which DNP causes hyperthermia is:
- A DNP inhibits ATP synthase, blocking proton return and increasing the electrochemical gradient to the point of mitochondrial membrane rupture
- B DNP activates uncoupling protein 1 in all tissues, not just brown fat, causing uncontrolled thermogenesis
- C DNP is a lipid-soluble weak acid that carries protons across the inner mitochondrial membrane in its protonated form, dissipating the proton gradient as heat without ATP synthesis ✓
- D DNP activates mitochondrial permeability transition pore (mPTP), releasing cytochrome c and triggering apoptotic cascade
Explanation
2,4-Dinitrophenol (DNP) is a lipid-soluble proton ionophore. At the acidic intermembrane space (pH ~7.0), DNP is protonated (becomes DNP-H+, neutral lipophilic form) and freely diffuses through the lipid bilayer to the more alkaline matrix (pH ~7.8) where it releases the proton. The deprotonated anionic DNP- then returns through the membrane, completing the cycle. This shunts the proton gradient as heat (uncouples respiration from phosphorylation), vastly accelerating substrate oxidation. The uncoupled ETC runs at maximum rate while ATP synthesis is negligible, producing massive heat — hyperthermia, sweating, tachycardia, and potentially fatal hyperpyrexia.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.