title: Mitochondrial metabolic regulation by GRP78.
abstract: Steroids, essential for mammalian survival, are initiated by cholesterol transport by steroidogenic acute regulatory protein (StAR). Appropriate protein folding is an essential requirement of activity. Endoplasmic reticulum (ER) chaperones assist in folding of cytoplasmic proteins, whereas mitochondrial chaperones fold only mitochondrial proteins. We show that glucose regulatory protein 78 (GRP78), a master ER chaperone, is also present at the mitochondria-associated ER membrane (MAM), where it folds StAR for delivery to the outer mitochondrial membrane. StAR expression and activity are drastically reduced following GRP78 knockdown. StAR folding starts at the MAM region; thus, its cholesterol fostering capacity is regulated by GRP78 long before StAR reaches the mitochondria. In summary, GRP78 is an acute regulator of steroidogenesis at the MAM, regulating the intermediate folding of StAR that is crucial for its activity.
authors.affiliation: Laboratory of Biochemistry and Cell Biology, Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.
authors.forename: Manoj
authors.initials: M
authors.lastname: Prasad
authors.affiliation: Laboratory of Biochemistry and Cell Biology, Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Pawlak
authors.affiliation: Laboratory of Biochemistry and Cell Biology, Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.; Anderson Cancer Institute, Memorial University Medical Center, Savannah, GA 31404, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Burak
authors.affiliation: Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA 30912, USA.
authors.forename: Elizabeth E
authors.identifier: 0000-0001-9508-5753
authors.initials: EE
authors.lastname: Perry
authors.affiliation: Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA 30912, USA.
authors.forename: Brendan
authors.identifier: 0000-0001-7147-0075
authors.initials: B
authors.lastname: Marshall
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
authors.forename: Randy M
authors.initials: RM
authors.lastname: Whittal
authors.affiliation: Laboratory of Biochemistry and Cell Biology, Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.; Anderson Cancer Institute, Memorial University Medical Center, Savannah, GA 31404, USA.
authors.forename: Himangshu S
authors.initials: HS
authors.lastname: Bose
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000098682:Steroidogenic Acute Regulatory Protein; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D002784:Cholesterol; D006360:Heat-Shock Proteins; D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP
keywords: GRP78; StAR; Steroids; mitochondria; mitochondria-associated ER membrane; mitochondrial chaperones