VDAC regulation: role of cytosolic proteins and mitochondrial lipids |
| |
Authors: | Tatiana K Rostovtseva Sergey M Bezrukov |
| |
Institution: | (1) Laboratory of Physical and Structural Biology, Program in Physical Biology, NICHD, National Institutes of Health, Bldg. 9, Rm. 1E-106, 9000 Rockville Pike, Bethesda, MD 20892, USA |
| |
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. |
| |
Keywords: | Apoptosis Mitochondria Mitochondria outer membrane Voltage dependent anion channel VDAC Channel gating Tubulin tBid Cardiolipin Lipid packing stress |
本文献已被 PubMed SpringerLink 等数据库收录! |
|