Question

Uncouplers of oxidative phosphorylation in mitochondria inhibit the coupling between the electron transport and phosphorylation reactions and thus inhibit ATP synthesis without affecting the respiratory chain and ATP synthase (H(+)-ATPase). Miscellaneous compounds are known to be uncouplers, but weakly acidic uncouplers are representative because they show very potent activities. The most potent uncouplers discovered so far are the hindered phenol SF 6847, and hydrophobic salicylanilide S-13, whic are active in vitro at concentrations in the 10 nM range. For induction of uncoupling, an acid dissociable group, bulky hydrophobic moiety and strong electron-withdrawing group are required. Weakly acidic uncouplers are considered to produce uncoupling by their protonophoric action in the H(+)-impermeable mitochondrial membrane. For exerting these effects, the stability of the respective uncoupler anions in the hydrophobic membrane is very important. High stability is achieved by delocalization of the polar ionic charge through uncoupler (chemical)-specific mechanisms. Such an action of weakly acidic uncouplers is characteristic of the highly efficient membrane targeting action of a nonsite-specific type of bioactive compound

Can I get some help with question 1. a and b please?

Answer 1

1.a. Chemical uncouplers delink the two processes of proton transfer and ATP production. Typically , an uncoupler diffuses into the matrix of mitochondri and releases a proton thus destabilizing the proton gradient. This dissipation of proton gradient leads to continuous proton cycling across the matrix without any production of ATP. A relatively low concentration of an uncoupling agent destablizes the proton gradient and diverts the protons from ATP synthase thus reducing ATP production. Since less number of ATPs are produced, a decrease in P/O ratio is seen.

b. Ingestion of uncouplers destabilises the proton gradient. The energy of the gradient is dissipated in the form of body heat which raises body temperature and in some cases ingestion of uncouplers may lead to hyperthermia. The increase in body temperature eventually leads to profuse sweating as the body tries to bring down the temperature through the cooling effect of sweat. In the presence of uncouplers, P/O ratio decreases steadily and reaches a point of minimum production of ATP .After sustained presence of an uncoupler, P/O ratio can reach dangerously close to 0 at which point the body enters hyperthermia which can lead to death.