α-Synuclein emerges as a potent regulator of VDAC-facilitated calcium transport

When the Parkinson9s disease (PD) related neuronal protein, alpha-synuclein (αSyn), is added to the reconstituted mitochondrial voltage-dependent anion channel (VDAC), it reversibly and partially blocks VDAC conductance by its acidic C-terminal tail. Using single-molecule electrophysiology of reconstituted VDAC we now demonstrate that, at CaCl2 concentrations below 150 mM, αSyn reverses the channel9s selectivity from anionic to cationic. Importantly, we find that the decrease in channel conductance upon its blockage by αSyn is hugely overcompensated by a favorable change in the electrostatic environment for calcium, making the blocked state orders-of-magnitude more selective for calcium and thus increasing its net flux. These findings reveal a new regulatory role of αSyn, with clear implications for both normal calcium signaling and PD-associated mitochondrial dysfunction.