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- W2912696632 abstract "The Voltage-Dependent Anion Channel (VDAC) forms a unique pathway across the mitochondrial outer membrane for small ions and water-soluble metabolites, such as ATP and ADP. Despite VDAC's involvement in both normal regulation of respiration and in a wide variety of mitochondria-associated pathologies, there are, surprisingly, no known pharmacological agents targeting VDAC. Emerging data show that VDAC actively controls metabolite fluxes via its interactions with cytosolic proteins. Among these, the small neuronal protein alpha-synuclein (aSyn) is a very potent regulator of VDAC, able to reversibly block this channel at nanomolar concentrations. Though generally recognized as a plaque-forming amyloid, aSyn is also known to cause mitochondrial dysfunction. We have shown that the efficiency of the aSyn-VDAC interaction is well described by a multistep mechanism of channel blocking, which includes membrane binding followed by capture in the VDAC pore. Based on this mechanism, we hypothesized that the architecture of a prospective VDAC inhibitor should fulfill two main requirements: possess a negatively charged disordered polypeptide C- or N-terminus (a pore blocking domain) and feature a mitochondrial membrane-binding domain. The hypothesized mechanism of VDAC inhibition is quite general; it does not require any specific interaction between the VDAC pore and inhibitor. Using aSyn as a template, we engineered three peptides and demonstrate that they all characteristically block VDAC reconstituted into planar lipid membranes in a controllable manner, thereby mimicking the action of aSyn. The VDAC blockage times induced by the synthetic peptides are comparable to aSyn-induced blockages, though the effective solution concentration required for synthetic blockers is 100 times higher than of aSyn (50nM). Our results demonstrate the general requirements of a VDAC inhibitor that will inform future development of mitochondria-targeting pharmacological tools." @default.
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- W2912696632 date "2019-02-01" @default.
- W2912696632 modified "2023-09-30" @default.
- W2912696632 title "Developing Specific Small-Peptide Inhibitors of Mitochondrial VDAC" @default.
- W2912696632 doi "https://doi.org/10.1016/j.bpj.2018.11.1452" @default.
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