Oligomycin is a natural antibiotic isolated from Streptomyces diastatochromogenes which inhibits mitochondrial H⁺-ATP synthase. It is primarily found to act as an inhibitor of mitochondrial respiration and swelling. This antibiotic is widely used as an inhibitor of oxidative phosphorylation.^1-2

Oligomycin inhibits the H⁺- ATP-synthase by binding to the Oligomycin sensitivity-conferring protein (OSCP) at the F(o) subunits 6 and 9 which are found in the stalk of the F₁F₀-ATPase complex. This binding blocks the proton conductance and inhibits the synthesis of mitochondrial ATP.^3-4 Because of its activity, it can also be used to reduce the number of parameters (such as ER Ca²⁺ release, exocytotoxicity and apopotosis) which are affected by mitochondrial depolarization.⁵

Oligomycin, at high concentrations may also inhibit the plasma membrane Na⁺-K⁺-ATPase. Interaction of Oligomycin with the Na⁺ occlusion site on the extracellular side of Na/K-ATPase, delays Na⁺ release to the extracellular side without inducing a conformational change. Although Oligomycin stimulated Na⁺ binding to Na⁺/K⁺-ATPase, it inhibited Na⁺/Na⁺ exchange, and did not affect either Na⁺-dependent AD/-ATP exchange or K⁺-dependent phosphatase activity.^6-16

These inhibitory properties have been attributed to its ability to occlude the transition of E₁~P (high energy intermediate) to E₂-P (low energy intermediate) by oligomycin binding to E₁~P.¹⁷