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

Int J Mol Sci. 2021 Jul 8;22(14):7358. doi: 10.3390/ijms22147358.

Abstract

The voltage-dependent anion channel (VDAC) is the primary regulating pathway of water-soluble metabolites and ions across the mitochondrial outer membrane. When reconstituted into lipid membranes, VDAC responds to sufficiently large transmembrane potentials by transitioning to gated states in which ATP/ADP flux is reduced and calcium flux is increased. 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 post-translational modifications of known inhibitors, and points the way toward the development of novel therapeutics targeting VDAC.

Keywords: ATP transport; beta-barrel channels; mitochondrial membranes; peripheral proteins; tubulin; voltage gating; voltage-dependent anion channel; α-synuclein.

Publication types

  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Anions / metabolism*
  • Calcium / metabolism
  • Cell Respiration / drug effects
  • Cell Respiration / physiology*
  • Fluoresceins / chemistry
  • Humans
  • Intrinsically Disordered Proteins / chemistry
  • Intrinsically Disordered Proteins / physiology*
  • Ion Channel Gating / drug effects
  • Ion Channel Gating / physiology
  • Kinetics
  • Mitochondrial Membranes / drug effects*
  • Mitochondrial Membranes / metabolism
  • Models, Molecular
  • Osmolar Concentration
  • Potassium Chloride / pharmacology
  • Protein Conformation
  • Protein Interaction Mapping
  • Protein Processing, Post-Translational
  • Protein Transport
  • Sequence Alignment
  • Sulfonic Acids / chemistry
  • Tubulin / chemistry
  • Tubulin / physiology*
  • Voltage-Dependent Anion Channels / antagonists & inhibitors*
  • Voltage-Dependent Anion Channels / chemistry
  • Voltage-Dependent Anion Channels / physiology
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / physiology*

Substances

  • Anions
  • Fluoresceins
  • Intrinsically Disordered Proteins
  • Sulfonic Acids
  • Tubulin
  • Voltage-Dependent Anion Channels
  • alexa fluor 488
  • alpha-Synuclein
  • Potassium Chloride
  • Calcium