Lipids in Regulation of the Mitochondrial Outer Membrane Permeability, Bioenergetics, and Metabolism
Tatiana K. Rostovtseva, David Hoogerheide, Amandine Rovini, Sergey M. Bezrukov
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 a less conventional view of the mitochondrial outer membrane (MOM) as a platform for cytosolic proteins to fulfill their ?auxiliary? function as potent regulators of the MOM permeability, realized 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 where the first step is a lipid-sensitive peripheral 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 lipiddependent manner. A proposed general model of VDAC inhibition explains satisfactorily how two very different but 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 enhances the availability of these molecules for the voltagesensitive interaction with VDAC. As the physiological significance of tubulin and α-syn association with mitochondrial membranes in cells is only starting to be recognized, 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 by which both cytosolic proteins regulate normal metabolite exchange through VDAC or cause mitochondrial dysfunction.
, Hoogerheide, D.
, Rovini, A.
and Bezrukov, S.
Lipids in Regulation of the Mitochondrial Outer Membrane Permeability, Bioenergetics, and Metabolism, Springer International, Bethesda, -1, [online], https://tsapps.nist.gov/publication/get_pdf.cfm?pub_id=922555
(Accessed March 4, 2024)