VDAC regulation: role of cytosolic proteins and mitochondrial lipids

Abstract

It was recently asserted that the voltage-dependent anion channel (VDAC) serves as a global regulator, or governor, of mitochondrial function (Lemasters and Holmuhamedov, Biochim Biophys Acta 1762:181-190, 2006). Indeed, VDAC, positioned on the interface between mitochondria and the cytosol (Colombini, Mol Cell Biochem 256:107-115, 2004), is at the control point of mitochondria life and death. This large channel plays the role of a "switch" that defines in which direction mitochondria will go: to normal respiration or to suppression of mitochondria metabolism that leads to apoptosis and cell death. As the most abundant protein in the mitochondrial outer membrane (MOM), VDAC is known to be responsible for ATP/ADP exchange and for the fluxes of other metabolites across MOM. It controls them by switching between the open and "closed" states that are virtually impermeable to ATP and ADP. This control has dual importance: in maintaining normal mitochondria respiration and in triggering apoptosis when cytochrome c and other apoptogenic factors are released from the intermembrane space into the cytosol. Emerging evidence indicates that VDAC closure promotes apoptotic signals without direct involvement of VDAC in the permeability transition pore or hypothetical Bax-containing cytochrome c permeable pores. VDAC gating has been studied extensively for the last 30 years on reconstituted VDAC channels. In this review we focus exclusively on physiologically relevant regulators of VDAC gating such as endogenous cytosolic proteins and mitochondrial lipids. Closure of VDAC induced by such dissimilar cytosolic proteins as pro-apoptotic tBid and dimeric tubulin is compared to show that the involved mechanisms are rather distinct. While tBid mostly modulates VDAC voltage gating, tubulin blocks the channel with the efficiency of blockage controlled by voltage. We also discuss how characteristic mitochondrial lipids, phospatidylethanolamine and cardiolipin, could regulate VDAC gating. Overall, we demonstrate that VDAC gating is not just an observation made under artificial conditions of channel reconstitution but is a major mechanism of MOM permeability control.

Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion

“…1-3). VDAC is a mitochondrial outer membrane protein and is the key component of the PTP complex, which is responsible for mitochondrial metabolite flux (28,29). VDAC regulation of the opening or closing of the PTP pore is a determinant in mitochondria-mediated apoptosis and in the generation of redox potential (25).…”

Functional dynamics in the voltage-dependent anion channel

“…This finding is interesting as lipid-protein interactions are known to be important for the structure and function of integral membrane proteins (47)(48)(49)(50)(51)(52). In particular, VDAC1 gating and ionic selectivity have been shown to be dependent on lipid composition (53). Our MD simulations of mVDAC1 in a lipid bilayer demonstrated that a charge on E73 causes a perturbation of the surrounding membrane (Fig.…”

A new approach to the problem of bulk-mediated surface diffusion

“…Reconstitution experiments with the voltage dependent anion channel (VDAC) from the outer mitochondrial membrane have demonstrated an unexpected role of the abundant water-soluble protein, dimeric tubulin, in physiological regulation of mitochondrial function. 27,28 The model, proposed for the VDAC interaction with tubulin and confirmed by a number of specially designed experiments, [29][30][31] suggests that the negatively charged disordered tail of tubulin enters the net positively charged VDAC pore and thus blocks it for metabolite transport. Importantly, it was found that this interaction is influenced by the membrane composition, being very sensitive to the lipid species used for bilayer formation in VDAC reconstitution.…”