title: Mitochondria-associated endoplasmic reticulum membrane (MAM) regulates steroidogenic activity via steroidogenic acute regulatory protein (StAR)-voltage-dependent anion channel 2 (VDAC2) interaction.
abstract: Steroid hormones are essential for carbohydrate metabolism, stress management, and reproduction and are synthesized from cholesterol in mitochondria of adrenal glands and gonads/ovaries. In acute stress or hormonal stimulation, steroidogenic acute regulatory protein (StAR) transports substrate cholesterol into the mitochondria for steroidogenesis by an unknown mechanism. Here, we report for the first time that StAR interacts with voltage-dependent anion channel 2 (VDAC2) at the mitochondria-associated endoplasmic reticulum membrane (MAM) prior to its translocation to the mitochondrial matrix. In the MAM, StAR interacts with mitochondrial proteins Tom22 and VDAC2. However, Tom22 knockdown by siRNA had no effect on pregnenolone synthesis. In the absence of VDAC2, StAR was expressed but not processed into the mitochondria as a mature 30-kDa protein. VDAC2 interacted with StAR via its C-terminal 20 amino acids and N-terminal amino acids 221-229, regulating the mitochondrial processing of StAR into the mature protein. In the absence of VDAC2, StAR could not enter the mitochondria or interact with MAM-associated proteins, and therefore steroidogenesis was inhibited. Furthermore, the N terminus was not essential for StAR activity, and the N-terminal deletion mutant continued to interact with VDAC2. The endoplasmic reticulum-targeting prolactin signal sequence did not affect StAR association with the MAM and thus its mitochondrial targeting. Therefore, VDAC2 controls StAR processing and activity, and MAM is thus a central location for initiating mitochondrial steroidogenesis.
authors.affiliation: From the Mercer University School of Medicine, Savannah, Georgia 31404.
authors.forename: Manoj
authors.initials: M
authors.lastname: Prasad
authors.affiliation: From the Mercer University School of Medicine, Savannah, Georgia 31404.
authors.forename: Jasmeet
authors.initials: J
authors.lastname: Kaur
authors.affiliation: From the Mercer University School of Medicine, Savannah, Georgia 31404.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Pawlak
authors.affiliation: Center of Excellence for Health Regeneration Biotechnology, Florida Biologix, University of Florida, Alachua, Florida 32615, Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida 32610.
authors.forename: Mahuya
authors.initials: M
authors.lastname: Bose
authors.affiliation: Department of Chemistry, University of Alberta, Alberta T6G2G2, Canada, and.
authors.forename: Randy M
authors.initials: RM
authors.lastname: Whittal
authors.affiliation: From the Mercer University School of Medicine, Savannah, Georgia 31404, Anderson Cancer Institute, Memorial University Medical Center, Savannah, Georgia 31404 bose_hs@mercer.edu bosehi1@memorialhealth.com.
authors.forename: Himangshu S
authors.initials: HS
authors.lastname: Bose
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D050996:Voltage-Dependent Anion Channel 2 / Q000235:genetics / Q000378:metabolism*; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D010750:Phosphoproteins; D050996:Voltage-Dependent Anion Channel 2; D000098682:Steroidogenic Acute Regulatory Protein
keywords: Cytochrome P450; Mitochondrial Metabolism; Progesterone; Steroidogenesis; Voltage-dependent Anion Channel (VDAC)