Mitochondrial proteases act on STARD3 to activate progesterone synthesis in human syncytiotrophoblast

Esparza-Perusquía, Mercedes; Olvera-Sánchez, Sofía; Flores-Herrera, Óscar; Flores‐Herrera, Héctor; Guevara-Flores, Alberto; Pardo, Juan Pablo; Espinosa-García, María Teresa; Martı́nez, Federico

doi:10.1016/j.bbagen.2014.10.009

Cited by 19 publications

(10 citation statements)

References 67 publications

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“…In most steroidogenic tissues, the transport of cholesterol from the outer to the inner mitochondrial membrane is mediated by StAR, which can be acutely stimulated by tissue-specific trophic hormones ( Miller, 2013 ); however, StAR is not expressed in human placenta ( Sugawara et al, 1995 ). Instead, StAR-like protein, STARD3 (or MLN64) ( Bose et al, 2000 ; Tuckey et al, 2004 ) as well as HSP60 are involved in mitochondrial cholesterol import in the placenta ( Tuckey, 2005 ; Olvera-Sanchez et al, 2011 ; Esparza-Perusquia et al, 2015 ; Monreal-Flores et al, 2017 ). In JEG-3 cells, HSP60 additionally participates in delivery of cholesterol to the metabolizing enzyme CYP11A1 ( Monreal-Flores et al, 2017 ).…”

Section: Steroid Hormonesmentioning

confidence: 99%

Physiology and Pathophysiology of Steroid Biosynthesis, Transport and Metabolism in the Human Placenta

2018

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The steroid hormones progestagens, estrogens, androgens, and glucocorticoids as well as their precursor cholesterol are required for successful establishment and maintenance of pregnancy and proper development of the fetus. The human placenta forms at the interface of maternal and fetal circulation. It participates in biosynthesis and metabolism of steroids as well as their regulated exchange between maternal and fetal compartment. This review outlines the mechanisms of human placental handling of steroid compounds. Cholesterol is transported from mother to offspring involving lipoprotein receptors such as low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SRB1) as well as ATP-binding cassette (ABC)-transporters, ABCA1 and ABCG1. Additionally, cholesterol is also a precursor for placental progesterone and estrogen synthesis. Hormone synthesis is predominantly performed by members of the cytochrome P-450 (CYP) enzyme family including CYP11A1 or CYP19A1 and hydroxysteroid dehydrogenases (HSDs) such as 3β-HSD and 17β-HSD. Placental estrogen synthesis requires delivery of sulfate-conjugated precursor molecules from fetal and maternal serum. Placental uptake of these precursors is mediated by members of the solute carrier (SLC) family including sodium-dependent organic anion transporter (SOAT), organic anion transporter 4 (OAT4), and organic anion transporting polypeptide 2B1 (OATP2B1). Maternal–fetal glucocorticoid transport has to be tightly regulated in order to ensure healthy fetal growth and development. For that purpose, the placenta expresses the enzymes 11β-HSD 1 and 2 as well as the transporter ABCB1. This article also summarizes the impact of diverse compounds and diseases on the expression level and activity of the involved transporters, receptors, and metabolizing enzymes and concludes that the regulatory mechanisms changing the physiological to a pathophysiological state are barely explored. The structure and the cellular composition of the human placental barrier are introduced. While steroid production, metabolism and transport in the placental syncytiotrophoblast have been explored for decades, few information is available for the role of placental-fetal endothelial cells in these processes. With regard to placental structure and function, significant differences exist between species. To further decipher physiologic pathways and their pathologic alterations in placental steroid handling, proper model systems are mandatory.

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Section: Steroid Hormonesmentioning

confidence: 99%

Physiology and Pathophysiology of Steroid Biosynthesis, Transport and Metabolism in the Human Placenta

2018

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“…In the second hit, which utilizes a STAR-independent process, recruited follicles synthesize small amounts of estrogen but ultimately accumulate excessive amounts of lipids resulting in destruction of the follicle prior to luteinization and progesterone production [26, 76, 84–86]. Factors responsible for the production of small amount of steroids include members of the START (STAR-related lipid-transfer) domain family (that have been reported to be involved in steroidogenesis) and oxysterols [43, 87–92]. …”

Section: Non-functional Star Protein Lipoid Cah and Physiological Cmentioning

confidence: 99%

Role of the steroidogenic acute regulatory protein in health and disease

et al. 2015

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Steroid hormones are an important class of regulatory molecules that are synthesized in steroidogenic cells of the adrenal, ovary, testis, placenta, brain and skin, and influence a spectrum of developmental and physiological processes. The steroidogenic acute regulatory protein (STAR) predominantly mediates the rate-limiting step in steroid biosynthesis, i.e., the transport of the substrate of all steroid hormones, cholesterol, from the outer to the inner mitochondrial membrane. At the inner membrane, cytochrome P450 cholesterol side chain cleavage enzyme cleaves the cholesterol side-chain to form the first steroid, pregnenolone, which is converted by a series of enzymes to various steroid hormones in specific tissues. Both basic and clinical evidence have demonstrated the crucial involvement of the STAR protein in the regulation of steroid biosynthesis. Multiple levels of regulation impinge on STAR action. Recent findings demonstrate that hormone-sensitive lipase, through its action on the hydrolysis of cholesteryl esters, plays an important role in regulating StAR expression and steroidogenesis which involve the liver X receptor pathway. Activation of the latter influences macrophage cholesterol efflux that is a key process in the prevention of atherosclerotic cardiovascular disease. Appropriate regulation of steroid hormones is vital for proper functioning of many important biological activities, which are also paramount for geriatric populations to live longer and healthier. This review summarizes the current level of understanding on tissue-specific and hormone-induced regulation of STAR expression and steroidogenesis, and provides insights into a number of cholesterol and/or steroid coupled physiological and pathophysiological consequences.

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“…Nuestro grupo de trabajo sugirió un modelo para la participación de la STARD3 en las mitocondrias de la placenta humana (Esparza-Perusquía et al, 2015) donde se propone que las gotas lipídicas contienen proteínas constituyentes de los complejos de fusión de membranas denominados SNARE (soluble N-ethylmaleimide-sensitive factor attachmentprotein receptor), entre las que incluyen las α-SNAP, syntaxina 3, 7 y 12, syntaxina-Binding Protein-2, syntaxina-Binding Protein-3, y VAMP-8, que podrían estar participando en el transporte del colesterol en las mitocondrias de la placenta humana. Se ha demostrado que la proteína SNAP promueve la interacción entre las gotas de lípidos y las mitocondrias, y que en las células esteroidogénicas las SNARE se expresan como Syntaxina-17, SNAP-23 y SNAP-25 (Grant et al, 1999;Steegmaier, Oorschot, Klumperman & Scheller, 2000;Jägerström et al, 2009).…”

Section: Sitios De Contacto Entre Las Membranas Mitocondrialesunclassified

“…Estas observaciones sugieren que las proteínas SNARE podrían contribuir en el mecanismo de transporte del colesterol a las mitocondrias esteroidogénicas, muy probablemente mediante la promoción de la interacción funcional entre las gotas de lípidos, el retículo endoplásmico, los endosomas y las mitocondrias. En las células del sinciciotrofoblasto, la proteína STARD3 puede ser incorporada en las mitocondrias a través de estos complejos y ser transformada a su forma activa por proteasas mitocondriales (Esparza-Perusquía et al, 2015), favoreciendo su incorporación o participación en los sitios de contacto (Uribe, Strauss & Martínez, 2003;Miller & Bose 2011) y promover el transporte del colesterol para la síntesis de la progesterona (Strauss, Kishida, Christenson, Fujimoto & Hiroi, 2003).…”

Section: Sitios De Contacto Entre Las Membranas Mitocondrialesunclassified

Aspectos generales del transporte de colesterol en la esteroidogénesis de la placenta humana

et al. 2019

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La placenta humana requiere de colesterol para sintetizar la progesterona que mantiene la relación entre el feto y la madre, lo que le permite concluir de manera exitosa el embarazo. La placenta incorpora el colesterol principalmente a través de las lipoproteínas de baja densidad (LDL) que se obtienen del torrente circulatorio materno por un mecanismo de endocitosis. A los endosomas que se generan en este proceso se les unen varias proteínas conformando los endosomas tardíos, que degradan las LDL y liberan el colesterol a las mitocondrias del sinciciotrofoblasto que lo transforman en pregnenolona y posteriormente en progesterona. Las proteínas de fusión de membranas denominados complejos SNARE participan en la liberación del colesterol en sitios de contacto específicos en donde se localizan las proteínas mitocondriales responsables de la esteroidogénesis.

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Mitochondrial proteases act on STARD3 to activate progesterone synthesis in human syncytiotrophoblast

Cited by 19 publications

References 67 publications

Physiology and Pathophysiology of Steroid Biosynthesis, Transport and Metabolism in the Human Placenta

Physiology and Pathophysiology of Steroid Biosynthesis, Transport and Metabolism in the Human Placenta

Role of the steroidogenic acute regulatory protein in health and disease

Aspectos generales del transporte de colesterol en la esteroidogénesis de la placenta humana

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