Molecular Regulation of the Mitochondrial F₁F_o-ATPsynthase: Physiological and Pathological Significance of the Inhibitory Factor 1 (IF ₁ )

Figure 3

Interaction of IF₁ with the F₁F_o-ATPsynthase. When mitochondria are in normal “energized” conditions (a), the F₁F_o-ATPsynthase can sustain physiological levels of ATP synthesis thanks to the presence of sufficient mitochondrial inner membrane potential; in this situation, the matrix pH is slightly basic, and IF₁ is predominantly present in its inactive, oligomeric form. When the electrochemical H⁺ gradient is lost, the F₁F_o-ATPsynthase starts hydrolysing the ATP imported from the cytosol to pump H⁺ back into the intermembrane space (b), restoring ΔΨ_𝑚. The augmented [H⁺] in the matrix causes a fall in pH that induces the disruption of IF₁ oligomers and the release of free active dimers. The binding of IF₁ dimers at the interface between 𝛼- and 𝛽-subunits of the F₁ domain is responsible for the selective inhibition of ATP hydrolysis (c–i), while its synthesis is not affected (c–ii). Active IF₁ is able to interact with two F₁ domains at the same time, inducing the dimerization of the F₁F_o-ATPsynthase (c), with subsequent increased enzymatic performance and cristae formation.

(a)

(b)

(c)