Modifiers of the oligomycin sensitivity of the mitochondrial F1F0-ATPase

The mitochondrial F₁F₀ complex is highly sensitive to macrolide antibiotics and especially targeted by oligomycins. These compounds bind to the membrane-embedded sector F₀ and block proton conductance through the inner membrane, thus inhibiting both ATP synthesis and hydrolysis. Oligomycin sensitivity is universally recognized as a clue of the functional integrity and matching between F₀ and F₁. Since oligomycin binding implies multiple interactions with amino acid residues of F₀, amino acid substitutions often affect the inhibition efficiency. Moreover, variegated factors spanning from membrane properties to xenobiotic incorporation and detachment of the oligomycin-insensitive F₁ sector can alter the oligomycin sensitivity of the enzyme complex. The overview on the multiple factors involved strengthens the link between altered oligomycin sensitivity and physiopathological conditions associated with defective ATPases. An improved understanding of the mechanisms involved may also favor drug design to counteract oxidative damage, which stems from most mitochondrial dysfunctions.