Essential role of alpha-synuclein in brain energy metabolism – implication to health and neurodegeneration
Alexey V. Berezhnov1,Marthe H.R. Ludtmann2, Andrey Y. Abramov2
1Institute of Cell Biophysics Russian Academy of Sciences, Pushchino, Russia
2UCL Institute of Neurology, London, UK
Despite a strong implication of misfolded α-synuclein in Parkinson’s disease, very little is known about the role of this protein in physiology. However, knowledge about a physiological role for unfolded, monomeric α-synuclein is limited. We have found an important function for alppha-synuclein in the regulation of ATP synthase activity. Applicatioon of extracellular monomeric α-synuclein enters the cell and localises to mitochondria, interacts with ATP synthase and modulates ATP synthase function. Using a combination of biochemical, live cell imaging and mitochondrial respiration analysis we found that lack of synuclein in mitochondria are uncoupled as characterised 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 monomeric α-synuclein is able to increase the ATP synthase activity that rescue the mitochondrial phenotypes observed in synuclein-deficiency. Overall, the data suggest that alpha-synuclein is a previously unrecognised physiological regulator of mitochondrial bioenergetics in brain cells through its ability to interact with ATP synthase and increase its efficiency.