BPS2026 – Estrogen receptor modulators affect mitochondrial physiology through the voltage-dependent anion channel

There are three mammalian voltage-dependent anion channel (VDAC) isoforms (VDAC1, VDAC2, and VDAC3) residing in the mitochondria outer membrane (MOM) where they conduct and regulate the fluxes of ions and metabolites between the cytosol and the mitochondria. VDACs interact with various cellular partners and pharmacologic compounds, thus dynamically controlling the MOM permeability and mitochondrial metabolism. The selective estrogen receptor modulators (SERMs) were designed to elicit tissue-dependent effects of endogenous estrogen (17-β-Estradiol, E2). A novel SERM, STX (analog of 4-OH-Tamoxifen) targets proopiomelanocortin (POMC) neurons and in a 5XFAD mice model of Alzheimer’s disease (AD) mitigates amyloid-β toxicity and improves mitochondrial function. A proteomic analysis revealed that a bifunctional STX (BF-STX) photo-crosslinks with all three VDAC isoforms ( p < 0.0001). We used a planar membrane electrophysiology approach to study how STX affects human recombinant VDAC1 and VDAC2’s functional properties—single-channel conductance, voltage gating, and ion selectivity. STX enhanced both isoforms’ voltage-gating with a K d of ∼15–50 nM and shifted VDAC’s closed states selectivities toward more anionic, as is VDAC’s open state. The surprising reverse in selectivity was confirmed in single-channel experiments on α-synuclein-VDAC interaction. Notably, STX did not change VDAC open state anionic selectivity, thus suggesting direct STX interaction with the lipid-facing surface of VDAC’s β-barrel. It has been implicated that E2 and other SERMs like tamoxifen target mitochondria. We found that E2 and tamoxifen also increase VDAC1 voltage gating but at micromolar concentrations. Using flow cytometry, we showed that E2 (1 μM) increases mitochondrial calcium while STX (100 nM) decreases it in HeLa cells. Our studies highlight the potential role of VDAC in E2-dependent regulation of mitochondria and provide insight into the therapeutic role of SERMs in AD and other neurodegenerative pathogeneses.