Effect of steroids on mitochondrial metabolite channel function and lipid membrane properties

Authors

• WM Rosencrans
• M Queralt-Martín
• A Rovini
• P Gurnev
• S Bezrukov
• T Rostovtseva

Abstract

There is accumulating evidence that endogenous steroids and synthetic steroid-based drugs are involved in regulating mitochondria physiology. The Voltage Dependent Anion Channel (VDAC), the major metabolite channel in the mitochondrial outer membrane (MOM), regulates the exchange of ions and water-soluble metabolites, such as ATP and ADP, across the MOM, thus governing mitochondrial respiration. VDAC reconstituted into planar lipid bilayers under an applied voltage characteristically switch from a high-conducting “open” state, that allows metabolites to pass, to a variety of low-conducting “closed” states that prevent metabolite flux. This process, called voltage-gating, involves structural rearrangements of VDAC. However, the mechanism behind VDAC gating remains elusive. Recent studies suggest that steroids may affect VDAC gating through interaction with the pore wall. However, functional data are missing and a molecular mechanism is unknown. Here we evaluate the effect of olesoxime, a neuroprotective hydrophobic cholesterol-derived drug, cholesterol, and allopregnanolone on VDAC voltage-gating properties using ion channel electrophysiology. We show that olesoxime enhances VDAC gating while cholesterol and allopregnanolone have no significant effect on gating properties. Suspecting a bilayer-dependent mechanism of olesoxime action, we examined the effect of olesoxime on gramicidin A (gA) kinetics. We use gA as a molecular probe of bilayer properties. We found that olesoxime does not affect gA lifetime while cholesterol and allopregnanolone increase it. These results indicate that olesoxime modulates VDAC gating likely by directly interacting with the channel-lipid interface, while the other steroids do not. Our study demonstrates a possibility of targeting VDAC for therapeutic outcomes utilizing hydrophobic small-molecule drugs.

Scientific Focus Area: Biomedical Engineering and Biophysics

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