Oligomycin proton transport inhibition

ADP phosphorylation is tightly coupled to electron transport. Shutting down one shuts down the other. It is well known that if ADP phosphorylation is inhibited by such compounds as oligomycin, electron transport also ceases. If the proton gradient is broken by a proton ionophore, however, such as 2,4-dinitrophenol, electron transport resumes at a rapid pace and no phosphorylation takes place. Such proton ionophores are also termed "uncouplers" of electron transport and ADP phosphorylation. Under normal conditions, the factors limiting ATP production are the pH gradient across the inner mitochondrial membrane and the cellular ADP/ATP ratio. An increase in the proton gradient shuts down phosphorylation and electron transport, whereas an increase in the ADP/ATP ratio stimulates both. Stimulation of oxidative phosphorylation by increases in cellular ADP concentration is termed respiratory control. 

ATP synthase also can be inhibited. Oligomycin and dicyclohexylcarbodiimide (DCCD) prevent the influx of protons through ATP synthase. If actively respiring mitochondria are exposed to an inhibitor of ATP synthase, the electron-transport chain ceases to operate. Indeed, this observation clearly illustrates that electron transport and ATP synthesis are normally tightly coupled. 

Inhibition of the electron transport chain in coupled mitochondria can occur at any of the three constituent functional processes electron transport per se, formation of ATP, or antiport translocation of ADP/ATP (Table 16-1). The best known inhibitor of the ADP/ATP translocase is atractyloside in the presence of which no ADP for phosphorylation is transported across the inner membrane to the ATP synthase and no ATP is transported out. In the absence of ADP phosphorylation the proton gradient is not reduced allowing other protons to be extruded into the intermembrane space because of the elevated [H+], and thus electron transfer is halted. Likewise the antibiotic oligomycin directly inhibits the ATP synthase, causing a cessation of ATP formation, buildup of protons in the intermembrane space, and a halt in electron transfer. Similarly, a blockade of complex I, III, or IV that inhibits electron flow down the chain to would also stop both ATP formation and ADP/ATP translocation across the inner mitochondrial membrane. 

Figure 3.27 shows the oxygen electrode traces from mitochondria incubated with malate and an inhibitor of ATP synthesis, with or without the addition of dinitrophenol as an uncoupler. Oligomycin is a therapeutically useless antibiotic produced by Streptomyces spp. that inhibits the transport of protons across the stalk of the primary particle. This results in inhibition of oxidation of both malate and succinate, because, if the protons cannot be transported back into the matrix, they will accumulate and... 

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