Regulation of Mitochondrial Respiration by VDAC is Enhanced by Membrane-Bound Inhibitors with Disordered Polyanionic C-Terminal Domains

Published

July 8, 2021

Author(s)

Tatiana Rostovtseva, Sergey M. Bezrukov, David Hoogerheide

Abstract

The voltage-dependent anion channel (VDAC) is the primary regulating transporter of water-soluble metabolites and ions across the mitochondrial outer membrane. When reconstituted into lipid membranes, VDAC responds to sufficiently large transmembrane potential by transitioning to gated states in which ATP/ADP flux is reduced and calcium flux increases. Two otherwise unrelated cytosolic proteins, tubulin and α-synuclein (αSyn), dock with VDAC by a novel mechanism in which the transmembrane potential draws their disordered, polyanionic C-terminal domains into and through the VDAC channel, thus physically blocking the pore. For both tubulin and αSyn, the blocked state is observed at much lower transmembrane potentials than VDAC gated states, such that in the presence of these cytosolic docking proteins, VDAC's sensitivity to transmembrane potential is dramatically increased. Remarkably, the features of the VDAC gated states relevant for bioenergetics—reduced metabolite flux and increased calcium flux—are preserved in the blocked state induced by either docking protein. The ability of tubulin and αSyn to modulate mitochondrial potential and ATP production in vivo is now supported by many studies. The common physical origin of the interactions of both tubulin and αSyn with VDAC leads to a general model of a VDAC inhibitor, facilitates predictions of the effect of posttranslational modifications of known inhibitors, and points the way toward development of novel therapeutics targeting VDAC.

Citation

International Journal of Molecular Sciences

Volume

22

Issue

14

Pub Type

Journals

Keywords

Voltage-dependent anion channel, tubulin, α-synuclein, voltage gating, ATP transport, mitochondrial membranes, peripheral proteins, beta-barrel channels

Citation

Rostovtseva, T. , Bezrukov, S. and Hoogerheide, D. (2021), Regulation of Mitochondrial Respiration by VDAC is Enhanced by Membrane-Bound Inhibitors with Disordered Polyanionic C-Terminal Domains, International Journal of Molecular Sciences (Accessed April 26, 2024)