How the mitochondrial F1FO-ATPase works when Ca2+ replaces Mg2+

The mitochondrial F1FO-ATPase is a reversible and biologically unique energy-transducing mechanism with coupled capabilities of H+ translocation across the hydrophobic FO domain and ATP synthesis/hydrolysis by the hydrophilic F1 domain. When the Ca2+ replaces the natural cofactor Mg2+ in the catalytic site [1], most of the enzyme features are preserved, namely the inhibition by the FO blockers DCCD and oligomycin, the oligomycin desensitization by thiol oxidation and the dependence on the electrochemical gradient. The two differently activated F-ATPases share the basic structure and function mechanism of H+ translocation. However, the mixed type inhibition of the Ca-F1FO-ATPase by ADP and azide suggests that, while the overall F1 catalysis is apparently divalent ion-independent, the intimate molecular mechanism of catalysis can be altered by the replacement of Mg2+ with Ca2+, probably due to the higher steric hindrance of Ca2+ with respect to Mg2+ in the cofactor binding sites [2]. Apparently, the two F-ATPases are two distinct functioning modes of the same F1FO complex. The putative involvement of enzyme in membrane permeability changes [3] hints that the Ca-dependent F1FO-ATPase modulation may open/close the permeability transition pore.