Membrane Lipid Composition Regulates Alpha-Synuclein Blockage of and Translocation through the Mitochondrial Voltage-Dependent Anion Channel

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Alpha-synuclein (α-syn), an intrinsically disordered protein, is a major component of Lewy bodies, a hallmark of Parkinson's disease (PD). α-Syn has been found to interact with both inner and outer mitochondrial membranes (MOM), impair electron transport complexes, and lead to neuronal apoptosis. Recently, using a channel reconstitution technique, we demonstrated that monomeric α-syn both reversibly blocks and translocates through the voltage-dependent anion channel (VDAC) at nanomolar concentrations. Considering VDAC's major role in regulating metabolite fluxes across the MOM, a functional interaction between α-syn and VDAC could be essential for physiological adaptation of mitochondria and dysfunction in PD. Here we show that the α-syn-VDAC interaction is modulated by membrane lipid composition relevant to MOM. We have found that the on-rate of VDAC blockage by α-syn increases up to 10-fold with increase of phosphoethanolamine (PE) content in phosphocholine (PC) membranes. Remarkably, the off-rate was also lipid-dependent, as seen by a 5 mV increase of the turnover potential separating regimes of blockage and translocation with the increase of PE content. We have also found that at physiologically low salt concentrations, the on-rates increase more than 10-fold compared to experiments performed in high salt, while translocation of α-syn through VDAC is impeded. α-Syn differential binding to lipid membranes was also tested using independent methods. These results suggest that the blockage of VDAC by α-syn involves α-syn interaction with the membrane and is governed by both hydrophobic and electrostatic components. Such evidence provides further support for our hypothesis that α-syn needs to bind to the membrane prior to blocking and translocating through the VDAC pore. We propose a new regulatory role of mitochondrial lipids in the (patho-)physiology of monomeric α-syn interaction with mitochondria.