Lipids in Regulation of the Mitochondrial Outer Membrane Permeability, Bioenergetics, and Metabolism

Abstract

The role of mitochondrial membranes in oxidative phosphorylation, energy production, calcium signaling, and mitochondrial metabolism is well established, especially with regard to lipid and steroid homeostasis, communication with other organelles, apoptosis, and human disease. Here we address the complementary role of the mitochondrial outer membrane (MOM) as a platform for cytosolic proteins to function as potent regulators of the MOM permeability through their direct functional interaction with the voltage-dependent anion channel (VDAC), the major MOM channel. Two abundant cytosolic proteins, dimeric tubulin and α-synuclein (α-syn), modulate fluxes of ATP/ADP and other water-soluble mitochondrial metabolites through VDAC. Their interaction with VDAC is a multistep process in which the first step is the lipid-sensitive binding to the MOM and the second is the voltage-dependent blockage of the VDAC pore. Both proteins induce characteristic rapid reversible blockages of VDAC reconstituted into planar lipid membranes with nanomolar efficiency and are thus able to effectively regulate ATP/ADP fluxes through VDAC in a lipid-dependent manner. A proposed general model of VDAC inhibition explains satisfactorily how two very different and otherwise unrelated proteins induce qualitatively similar blockages of reconstituted VDAC. In in vitro biophysical experiments, tubulin and α-syn display similar lipid-dependent membrane-binding properties, which make these proteins well suited for targeting the MOM and strongly enhance the availability of these molecules for the voltage-sensitive interaction with VDAC. As the physiological significance of the association of tubulin and α-syn with mitochondrial membranes in cells is only beginning to be appreciated, we propose a new role of mitochondrial lipids in the control of MOM permeability. Overall, the emerging data indicate that the physiological conditions in the cell, such as the expression level of α-syn, the ratio between dimeric and polymerized tubulin in the cytosol, cytosolic pH, MOM lipid composition, level of lipid peroxidation, and potential across the MOM, strongly determine the efficiency with which both cytosolic proteins regulate normal metabolite exchange through VDAC or cause mitochondrial dysfunction.