From the Ca²⁺-activated F₁F_O-ATPase to the mitochondrial permeability transition pore: an overview

Based on recent advances on the Ca²⁺-activated F₁F_O-ATPase features, a novel multistep mechanism involving the mitochondrial F₁F_O complex in the formation and opening of the still enigmatic mitochondrial permeability transition pore (MPTP), is proposed. MPTP opening makes the inner mitochondrial membrane (IMM) permeable to ions and solutes and, through cascade events, addresses cell fate to death. Since MPTP forms when matrix Ca²⁺ concentration rises and ATP is hydrolyzed by the F₁F_O-ATPase, conformational changes, triggered by Ca²⁺ insertion in F₁, may be transmitted to F_O and locally modify the IMM curvature. These events would cause F₁F_O-ATPase dimer dissociation and MPTP opening.