Ca²⁺ as cofactor of the mitochondrial H⁺‐translocating F₁F_O‐ATP(hydrol)ase

Abstract

The mitochondrial F1FO‐ATPase in the presence of the natural cofactor Mg2+ acts as the enzyme of life by synthesizing ATP, but it can also hydrolyze ATP to pump H+. Interestingly, Mg2+ can be replaced by Ca2+, but only to sustain ATP hydrolysis and not ATP synthesis. When Ca2+ inserts in F1, the torque generation built by the chemomechanical coupling between F1 and the rotating central stalk was reported as unable to drive the transmembrane H+ flux within FO. However, the failed H+ translocation is not consistent with the oligomycin‐sensitivity of the Ca2+‐dependent F1FO‐ATP(hydrol)ase. New enzyme roles in mitochondrial energy transduction are suggested by recent advances. Accordingly, the structural F1FO‐ATPase distortion driven by ATP hydrolysis sustained by Ca2+ is consistent with the permeability transition pore signal propagation pathway. The Ca2+‐activated F1FO‐ATPase, by forming the pore, may contribute to dissipate the transmembrane H+ gradient created by the same enzyme complex.

Molecular and Supramolecular Structure of the Mitochondrial Oxidative Phosphorylation System: Implications for Pathology

“…The hydrolytic function of the F 1 F O -ATPase, namely ATP hydrolysis, can be sustained by metal divalent cations different from the natural cofactor Mg 2+ , such as Ca 2+ , which is unable to activate the enzyme complex in the opposite function of ATP synthesis [192][193][194][195]. Interestingly, Ca 2+ rise in the mitochondrial matrix initiates a cascade of events which lead to cell death.…”

“…Interestingly, Ca 2+ rise in the mitochondrial matrix initiates a cascade of events which lead to cell death. So, in recent times Ca 2+ binding to the F 1 F O -ATPase in replacement of Mg 2+ , an event which can easily occur in the presence of relatively high Ca 2+ concentrations in mitochondria, since the enzyme affinity for Ca 2+ is lower than that for Mg 2+ [193,196], has been associated with the mPTP opening [192,195,[197][198][199].…”