Monomeric Alpha-Synuclein Exerts a Physiological Role on Brain ATP Synthase

Misfolded alpha-synuclein is a key factor in the pathogenesis of Parkinson's disease (PD). However, knowledge about a physiological role for the native, unfolded alpha-synuclein is limited. Using brains of mice lacking alpha-, beta-, and gamma-synuclein, we report that extracellular monomeric alpha-synuclein enters neurons and localizes to mitochondria, interacts with ATP synthase subunit alpha, and modulates ATP synthase function. Using a combination of biochemical, live-cell imaging and mitochondrial respiration analysis, we found that brain mitochondria of alpha-, beta-, and gamma-synuclein knock-out mice are uncoupled, as characterized by increased mitochondrial respiration and reduced mitochondrial membrane potential. Furthermore, synuclein deficiency results in reduced ATP synthase efficiency and lower ATP levels. Exogenous application of low unfolded alpha-synuclein concentrations is able to increase the ATP synthase activity that rescues the mitochondrial phenotypes observed in synuclein deficiency. Overall, the data suggest that alpha-synuclein is a previously unrecognized physiological regulator of mitochondrial bioenergetics through its ability to interact with ATP synthase and increase its efficiency. This may be of particular importance in times of stress or PD mutations leading to energy depletion and neuronal cell toxicity.