High-Affinity Interaction with VDAC Links Cytosolic Proteins to Mitochondrial Regulation in Health, Cancer, and Neurodegeneration

Abstract

We address the question of how mitochondria control cell survival and cell death by studying the voltage-dependent anion channel (VDAC). VDAC, the major channel of the mitochondrial outer membrane (MOM), is a well-recognized key conduit for ATP and other bioenergetics metabolites fluxes across MOM. We have found that dimeric tubulin, the subunit of microtubule, induces highly efficient reversible blockage of VDAC reconstituted into planar lipid membranes. Although the tubulin-blocked state still conducts small ions, it is virtually impermeable to ATP. We propose that by modulating VDAC permeability for ATP and other respiratory substrates, tubulin controls mitochondrial respiration. These findings are supported by experiments with isolated mitochondria and human hepatoma cells, thus uncovering a mechanism of regulation of mitochondrial energetics by free tubulin and also suggesting how cancer cells preferentially use inefficient glycolysis rather than oxidative phosphorylation (the Warburg effect).We also found a functional interaction between VDAC and α-synuclein (α-syn), an intrinsically disordered neuronal protein intimately associated with Parkinson disease (PD) pathogenesis. Importantly, in addition to regulation of VDAC permeability by α-syn, our data indicate that VDAC facilitates translocation of α-syn across MOM where it could target complexes of the mitochondrial respiratory chain in the inner membrane. Supporting our in vitro experiments, a yeast model of PD shows that α-syn toxicity in yeast depends on VDAC. Considering that VDAC is a major conduit for respiratory substrates across the mitochondrial outer membrane, we conclude that the α-syn/VDAC functional interaction reveals the elusive physiological and pathophysiological roles for monomeric α-syn in PD and also in general neurodegeneration.