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.
Highlights
The crucial role of mitochondrial outer membrane (MOM) permeability in maintaining an efficient metabolite exchange between mitochondria and cytoplasm in normal respiration is well-established, with voltage-dependent anion channel (VDAC) recognized as the MOM key metabolite pathway and regulator
Considering VDAC’s unique role in mitochondrial physiology, this is a very unfortunate situation. We address this problem by discussing the molecular mechanism of VDAC regulation by two potent, but structurally and functionally distinct, cytosolic proteins: dimeric tubulin and α-synuclein
When αSyn or dimeric tubulin are added to the bulk solutions surrounding a planar lipid membrane (PLM) with reconstituted VDAC, they both induce characteristic fast blockages of channel conductance (Figure 4B,C)
Summary
The crucial role of mitochondrial outer membrane (MOM) permeability in maintaining an efficient metabolite exchange between mitochondria and cytoplasm in normal respiration is well-established, with VDAC recognized as the MOM key metabolite pathway and regulator. A major reason for uncertainty regarding the physiological role of the VDAC gating mechanism for regulation of MOM permeability, is the source, magnitude, and regulation of the outer membrane potential in vivo. This issue has been addressed in multiple papers (see discussions in [3,19,20,21]). We address this problem by discussing the molecular mechanism of VDAC regulation by two potent, but structurally and functionally distinct, cytosolic proteins: dimeric tubulin and α-synuclein (αSyn). We hope that answers to these questions will guide researchers in finding new potent endogenous regulators and inhibitors of VDAC and chart a path towards a long-overdue VDAC pharmacology
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