The new role of FF ATP synthase in mitochondria-mediated neurodegeneration and neuroprotection.

The mitochondrial FF ATP synthase is one of the most abundant proteins of the mitochondrial inner membrane, which catalyzes the final step of oxidative phosphorylation to synthesize ATP from ADP and Pi. ATP synthase uses the electrochemical gradient of protons (Δμ) across the mitochondrial inner membrane to synthesize ATP. Under certain pathophysiological conditions, ATP synthase can run in reverse to hydrolyze ATP and build the necessary Δμ across the mitochondrial inner membrane. Tight coupling between these two processes, proton translocation and ATP synthesis, is achieved by the unique rotational mechanism of ATP synthase and is necessary for efficient cellular metabolism and cell survival. The uncoupling of these processes, dissipation of mitochondrial inner membrane potential, elevated levels of ROS, low matrix content of ATP in combination with other cellular malfunction trigger the opening of the mitochondrial permeability transition pore in the mitochondrial inner membrane. In this review we will discuss the new role of ATP synthase beyond oxidative phosphorylation. We will highlight its function as a unique regulator of cell life and death and as a key target in mitochondria-mediated neurodegeneration and neuroprotection.