title: Decreased cytochrome c oxidase IV expression reduces steroidogenesis.
abstract: Steroidogenic acute regulatory protein facilitates the translocation of cholesterol to the inner mitochondrial membrane, thereby initiating steroidogenesis. At the inner mitochondrial membrane, cytochrome P450 side-chain cleavage enzyme converts cholesterol to pregnenolone, an oxidative process requiring electrons from NADPH. Pregnenolone then serves as the substrate for the formation of progesterone or dehydroepiandrosterone by downstream enzymes. Studies have shown that cigarette smoke (CS) influences steroid hormone levels. To better understand the underlying mechanisms, we used a mouse model to study the effects of chronic CS exposure on steroidogenesis. Through radioimmunoassay and metabolic conversion assays, we found that CS reduced progesterone and dehydroepiandrosterone without affecting cytochrome P450 side-chain cleavage enzyme or 3β-hydroxysteroid dehydrogenase 2 expression. However, CS did reduce expression of cytochrome c oxidase IV (COX IV), a component of the mitochondrial complex that serves as the last enzyme in the electron transport chain. Small interfering RNA-mediated COX IV knockdown indeed decreased progesterone synthesis in steroidogenic cells. In summary, COX IV likely plays a role in steroidogenesis, and passive smoking may negatively affect steroidogenesis by disrupting the electron transport chain.
authors.affiliation: Department of Biochemistry, Mercer University School of Medicine and Memorial University Medical Center, Hoskins Research Building, 4700 Waters Ave., Savannah, GA 31404, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Pawlak
authors.forename: Manoj
authors.initials: M
authors.lastname: Prasad
authors.forename: Kevin A
authors.initials: KA
authors.lastname: McKenzie
authors.forename: John P
authors.initials: JP
authors.lastname: Wiebe
authors.forename: C Gary
authors.initials: CG
authors.lastname: Gairola
authors.forename: Randy M
authors.initials: RM
authors.lastname: Whittal
authors.forename: Himangshu S
authors.initials: HS
authors.lastname: Bose
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003687:Dehydroepiandrosterone / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015536:Down-Regulation / Q000235:genetics; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D011284:Pregnenolone / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011374:Progesterone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011897:Random Allocation; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism*; D013256:Steroids
chemical_list: D013256:Steroids; D003687:Dehydroepiandrosterone; D011374:Progesterone; D011284:Pregnenolone; D003576:Electron Transport Complex IV