σ-1 Receptor at the Mitochondrial-Associated Endoplasmic Reticulum Membrane Is Responsible for Mitochondrial Metabolic Regulation

Abstract

The mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) is a small section of the outer mitochondrial membrane tethered to the ER by lipid and protein filaments. One such MAM protein is the -1 receptor, which contributes to multiple signaling pathways. We found that short interfering RNA-mediated knockdown of -1 reduced pregnenolone synthesis by 95% without affecting expression of the inner mitochondrial membrane resident enzyme, 3-␤-hydroxysteroid dehydrogenase 2. To explore the underlying mechanism of this effect, we generated a series of -receptor ligands: 5,6-dimethoxy-3-methyl-N-phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamide (KSCM-1), 3-methyl-N-phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamide (KSCM-5), and 6-methoxy-3-methyl-Nphenyl-N-(3-(piperidin-1-yl) propyl)benzofuran-2-carboxamide (KSCM-11) specifically bound to -1 in the nanomolar range, whereas KSCM-5 and KSCM-11 also bound to -2. Treatment of cells with the KSCM ligands led to decreased cell viability, with KSCM-5 having the most potent effect followed by KSCM-11. KSCM-1 increased -1 expression by 4-fold and progesterone synthesis, whereas the other compounds decreased progesterone synthesis. These differences probably are caused by ligand molecular structure. For example, KSCM-1 has two methoxy substituents at C-5 and C-6 of the benzofuran ring, whereas KSCM-11 has one at C-6. KSCM ligands or -1 knockdown did not alter the expression of ER resident enzymes that synthesize steroids. However, coimmunoprecipitation of the -1 receptor pulled down voltage-dependent anion channel 2 (VDAC2), whose expression was enhanced by KSCM-1. VDAC2 plays a key role in cholesterol transport into the mitochondria, suggesting that the -1 receptor at the MAM coordinates with steroidogenic acute regulatory protein for cholesterol trafficking into the mitochondria for metabolic regulation.

Sigma-1 Receptor Regulates Early Steps of Viral RNA Replication at the Onset of Hepatitis C Virus Infection

“…It is noteworthy that S1R-deficient primary hippocampal cultures display significant changes in the levels of expression of cellular genes related to cholesterol and fatty acid metabolism (64). Moreover, a recent study shows that steroid biosynthesis, which depends on the immediate availability of cholesterol at the outer mitochondrial membrane, is defective in S1R-deficient MA-10 cells (65). These data, together with the recognized ability of S1R to modulate cholesterol homeostasis in different cellular compartments (66) and the ability of S1R to bind cholesterol and sphingolipids (33), raise the possibility that S1R provides these and other lipids to the nascent replication complexes through nonvesicular transport to specific areas of the ER where viral proteins accumulate, a notion that is supported by our confocal microscopy data (Fig.…”

The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems

“…[55] reported that the Sig-1R can interact with VDAC and contributes to the regulation of mitochondrial pregnenolone synthesis. Studies have shown that the VDAC on the outer mitochondrial membrane may interact with steroidogenic acute regulatory protein [56], another exclusive outer mitochondrial membrane protein, and enhances the cholesterol import.…”

VDAC2-specific cellular functions and the underlying structure

“…In terms of the other tissues, the picture is less clear and some potentially important tissues are not included in the tissue surveys. For example, recent evidence indicated that VDAC2 might be important for the mitochondrial steps of steroid hormone production [35,36] and VDAC2 protein seems to be enriched in the testis and placenta but the steroid producing cells of the adrenal cortex have not been evaluated.…”