Mitochondrial F-ATP Synthase and Its Transition into an Energy-Dissipating Molecular Machine

The mitochondrial F-ATP synthase is the principal energy-conserving nanomotor of cells that harnesses the proton motive force generated by the respiratory chain to make ATP from ADP and phosphate in a process known as oxidative phosphorylation. In the energy-converting membranes, F-ATP synthase is a multisubunit complex organized into a membrane-extrinsic F₁ sector and a membrane-intrinsic F_O domain, linked by central and peripheral stalks. Due to its essential role in the cellular metabolism, malfunction of F-ATP synthase has been associated with a variety of pathological conditions, and the enzyme is now considered as a promising drug target for multiple disease conditions and for the regulation of energy metabolism. We discuss structural and functional features of mitochondrial F-ATP synthase as well as several conditions that partially or fully inhibit the coupling between the F₁ catalytic activities and the F_O proton translocation, thus decreasing the cellular metabolic efficiency and transforming the enzyme into an energy-dissipating structure through molecular mechanisms that still remain to be defined.