| Uncouplers of oxidative phosphorylation dissipate the proton gradient by transporting protons back into mitochondria, bypassing the ATP synthase. This stimulates respiration, because the system makes a futile attempt to restore the proton gradient by oxidizing more fuel and pumping more protons out of mitochondria. Uncouplers are typically hydrophobic compounds, either weak acids or bases, with pKa near pH 7. The classical uncoupler, 2,4-dinitrophenol (DNP) (Fig. 8.14), accepts a proton on the outer, more acidic side of the inner mitochondrial membrane. Because of its hydrophobicity, it may then freely diffuse through the inner mitochondrial membrane. When it reaches the matrix side, it encounters a more basic pH, and the proton is released, effectively discharging the pH gradient. Other uncouplers include preservatives and antimicrobial agents, such as pentachlorophenol and p-cresol.
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