Isocitrate dehydrogenase type 2 (IDH2) is part of a multiprotein complex for placental steroidogenesis. (November 2019)

• Record Type: Journal Article
• Authors: Urban-Sosa, Viviana Andrea; Olvera-Sánchez, Sofia; Barrera, David; Aragón-Hernández, Juan Pablo; Flores-Herrera, Oscar; Martínez, Federico
• Is Part Of: Placenta. Volume 87(2020)
• Page Start: 30
• Page End: 37
• Publication Date: 2019-11
• Subjects: Syncytiotrophoblast -- Mitochondria -- Isocitrate dehydrogenase 2 -- Steroidogenic contact sites -- Progesterone synthesis; Placenta -- Periodicals; Reproduction -- Periodicals; Placenta -- Periodicals; Placenta -- Périodiques; Reproduction -- Périodiques; 612.63
• DOI: 10.1016/j.placenta.2019.09.008
• Languages: English
• ISSNs: 0143-4004

Abstract

Abstract: Background: Human syncytiotrophoblast mitochondria require the activity of the isocitrate dehydrogenase type 2 (IDH2) to obtain reduced coenzymes for progesterone (P4) synthesis. Data from the literature indicate that mitochondrial steroidogenic contact sites transform efficiently cholesterol into P4. In this research, we identified the IDH2 as a member of the steroidogenic contact site and analyzed the steroidogenic role of its activity. Method: Human syncytiotrophoblast mitochondria were isolated by differential centrifugation, and steroidogenic contact sites were obtained by osmotic shock and sucrose gradient ultracentrifugation. In-gel native activity assay, mass spectroscopy, and western blot were used to identify the association of proteins and their activities. P4 was determined by immunofluorescence. Results: The IDH2 was mainly identified in steroidogenic contact sites, and its activity was associated with a complex of proteins with an apparent molecular mass of ~590 kDa. Mass spectroscopy showed many groups of proteins with several metabolic functions, including steroidogenesis and ATP synthesis. The IDH2 activity was coupled to P4 synthesis since in the presence of Ca 2+ or Na2 SeO3, inhibitors of the IDH2, the P4 production decreased. Conclusions: The human syncytiotrophoblast mitochondria build contact sites for steroidogenesis. The IDH2, a non-membrane protein, supplies the NADPH required for the synthesis of P4 in a complex (steroidosome) that associate the proteins required to transform efficiently cholesterol into P4, which is necessary in pregnancy to maintain the relationship between mother and fetus. General significance: The IDH2 is proposed as a check point in the regulation of placental steroidogenesis. Highlights: IDH2 is a soluble protein present in the mitochondrial steroidogenic contact sites. Western blot shows an increase of steroidogenic proteins and IDH2 in contact sites. Immunoprecipitation shows that IDH2 is associated with the P450scc chain. Ca 2+ inhibits the IDH2 activity and P4 synthesis in steroidogenic contact sites. A steroidogenesis model is proposed for contact sites of human placenta.