title: An Outer Mitochondrial Translocase, Tom22, Is Crucial for Inner Mitochondrial Steroidogenic Regulation in Adrenal and Gonadal Tissues.
abstract: After cholesterol is transported into the mitochondria of steroidogenic tissues, the first steroid, pregnenolone, is synthesized in adrenal and gonadal tissues to initiate steroid synthesis by catalyzing the conversion of pregnenolone to progesterone, which is mediated by the inner mitochondrial enzyme 3β-hydroxysteroid dehydrogenase 2 (3βHSD2). We report that the mitochondrial translocase Tom22 is essential for metabolic conversion, as its knockdown by small interfering RNA (siRNA) completely ablated progesterone conversion in both steroidogenic mouse Leydig MA-10 and human adrenal NCI cells. Tom22 forms a 500-kDa complex with mitochondrial proteins associated with 3βHSD2. Although the absence of Tom22 did not inhibit mitochondrial import of cytochrome P450scc (cytochrome P450 side chain cleavage enzyme) and aldosterone synthase, it did inhibit 3βHSD2 expression. Electron microscopy showed that Tom22 is localized at the outer mitochondrial membrane (OMM), while 3βHSD2 is localized at the inner mitochondrial space (IMS), where it interacts through a specific region with Tom22 with its C-terminal amino acids and a small amino acid segment of Tom22 exposed to the IMS. Therefore, Tom22 is a critical regulator of steroidogenesis, and thus, it is essential for mammalian survival.
authors.affiliation: Department of Biochemistry, Mercer University School of Medicine, Savannah, Georgia, USA.
authors.forename: Maheshinie
authors.initials: M
authors.lastname: Rajapaksha
authors.affiliation: Department of Biochemistry, Mercer University School of Medicine, Savannah, Georgia, USA.
authors.forename: Jasmeet
authors.initials: J
authors.lastname: Kaur
authors.affiliation: Department of Biochemistry, Mercer University School of Medicine, Savannah, Georgia, USA.
authors.forename: Manoj
authors.initials: M
authors.lastname: Prasad
authors.affiliation: Department of Biochemistry, Mercer University School of Medicine, Savannah, Georgia, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Pawlak
authors.affiliation: Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Marshall
authors.affiliation: Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, Georgia, USA.
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Perry
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Randy M
authors.initials: RM
authors.lastname: Whittal
authors.affiliation: Department of Biochemistry, Mercer University School of Medicine, Savannah, Georgia, USA Anderson Cancer Institute, Memorial University Medical Center, Savannah, Georgia, USA bose_hs@mercer.edu.
authors.forename: Himangshu S
authors.initials: HS
authors.lastname: Bose
mesh_terms: D000311:Adrenal Glands / Q000166:cytology / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D007985:Leydig Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000648:ultrastructure; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D008969:Molecular Sequence Data; D011374:Progesterone / Q000378:metabolism*; D011375:Progesterone Reductase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D060066:Protein Interaction Maps; D021381:Protein Transport; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D016415:Sequence Alignment
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D034741:RNA, Small Interfering; C489971:TOMM22 protein, human; C000609269:Tom22 protein, mouse; D011374:Progesterone; C533068:3 beta-hydroxysteroid dehydrogenase type II; D011375:Progesterone Reductase