title: Steroid hormone synthesis in mitochondria.
abstract: Mitochondria are essential sites for steroid hormone biosynthesis. Mitochondria in the steroidogenic cells of the adrenal, gonad, placenta and brain contain the cholesterol side-chain cleavage enzyme, P450scc, and its two electron-transfer partners, ferredoxin reductase and ferredoxin. This enzyme system converts cholesterol to pregnenolone and determines net steroidogenic capacity, so that it serves as the chronic regulator of steroidogenesis. Several other steroidogenic enzymes, including 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase and aldosterone synthase also reside in mitochondria. Similarly, the mitochondria of renal tubular cells contain two key enzymes participating in the activation and degradation of vitamin D. The access of cholesterol to the mitochondria is regulated by the steroidogenic acute regulatory protein, StAR, serving as the acute regulator of steroidogenesis. StAR action requires a complex multi-component molecular machine on the outer mitochondrial membrane (OMM). Components of this machine include the 18 kDa translocator protein (TSPO), the voltage-dependent anion chanel (VDAC-1), TSPO-associated protein 7 (PAP7, ACBD3), and protein kinase A regulatory subunit 1α (PKAR1A). The precise fashion in which these proteins interact and move cholesterol from the OMM to P450scc, and the means by which cholesterol is loaded into the OMM, remain unclear. Human deficiency diseases have been described for StAR and for all the mitochondrial steroidogenic enzymes, but not for the electron transfer proteins or for the components of the cholesterol import machine.
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143-1346, USA; Division of Endocrinology, University of California San Francisco, San Francisco, CA 94143-1346, USA. Electronic address: wlmlab@ucsf.edu.
authors.forename: Walter L
authors.initials: WL
authors.lastname: Miller
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000305:Adrenal Cortex Hormones / Q000096:biosynthesis*; D001692:Biological Transport / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000378:metabolism; D012739:Gonadal Steroid Hormones / Q000096:biosynthesis*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000201:enzymology / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010926:Placental Hormones / Q000096:biosynthesis*; D011284:Pregnenolone / Q000096:biosynthesis; D018079:Receptors, GABA / Q000378:metabolism; D014807:Vitamin D / Q000378:metabolism; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: C449459:ACBD3 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000305:Adrenal Cortex Hormones; D012739:Gonadal Steroid Hormones; D008565:Membrane Proteins; D010750:Phosphoproteins; D010926:Placental Hormones; D018079:Receptors, GABA; C499229:TSPO protein, human; C494762:VDAC1 protein, human; D000098682:Steroidogenic Acute Regulatory Protein; D014807:Vitamin D; D011284:Pregnenolone; D002784:Cholesterol; D002786:Cholesterol Side-Chain Cleavage Enzyme; D050995:Voltage-Dependent Anion Channel 1; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
keywords: 1,25 dihydroxy vitamin D (calcitriol); 1,25(OH)(2)D; 18kDa translocator protein; 3-hydroxy-3-methylglutaryl co-enzyme A; 3β-hydroxysteroid dehydrogenase; 3βHSD; ACAT; ACTH; ANT; CRAC; Cholesterol side chain cleavage; Cholesterol transport; ER; FAD; HDL; HMGCoA; HSL; IMM; IMS; Km; LAL; LDL; LH; MENTAL; MENTHO; MLN64; MLN64 N-terminal; MLN64 N-terminal domain homologue; Michaelis constant; NADPH; NPC; Niemann Pick type C; OMM; Outer mitochondrial membrane; P450scc; PAP7; PBR; PCP; PKA; PKAR1A; PRAX1; PTH; SF1; SOAT; SR-B1; SREBPs; START; StAR; StAR-related lipid transfer domain; Steroidogenesis; Steroidogenic acute regulatory protein; TSPO; TSPO-associated protein 1; TSPO-associated protein 7 (ACBD3); VDAC1; Vitamin D; acyl transferase; adenine nucleotide transporter; adrenocorticotropic hormone; cholesterol recognition amino acid consensus domain; endoplasmic reticulum; flavin adenine dinucleotide; high density lipoproteis; hormone-sensitive neutral lipase; inner mitochondrial membrane; intramembranous space; low-density lipoproteins; luteinizing hormone; lysosomal acid lipase; metastatic lymph node clone 64; mitochondrial cytochrome P450 specific for cholesterol side-chain cleavage; nicotinamide adenine dinucleotide phosphate; outer mitochondrial membrane; parathyroid hormone; peripheral benzodiazepine receptor; phosphate carrier protein; protein kinase A; protein kinase A regulatory subunit 1α; scavenger receptor B1; steroidogenic acute regulatory protein; steroidogenic factor 1; sterol O-acetyltransferase; sterol regulatory element binding proteins; voltage-dependent anion channel