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Ceramide-induced BOK promotes mitochondrial fission in preeclampsia

dc.contributor.authorAusman, Jonathan
dc.contributor.authorAbbade, Joelcio [UNESP]
dc.contributor.authorErmini, Leonardo
dc.contributor.authorFarrell, Abby
dc.contributor.authorTagliaferro, Andrea
dc.contributor.authorPost, Martin
dc.contributor.authorCaniggia, Isabella
dc.contributor.institutionSinai Health System
dc.contributor.institutionUniversity of Toronto
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionHospital for Sick Children
dc.date.accessioned2018-12-11T17:18:04Z
dc.date.available2018-12-11T17:18:04Z
dc.date.issued2018-03-01
dc.description.abstractMitochondria are in a constant balance of fusing and dividing in response to cellular cues. Fusion creates healthy mitochondria, whereas fission results in removal of non-functional organelles. Changes in mitochondrial dynamics typify several human diseases. However, the contribution of mitochondrial dynamics to preeclampsia, a hypertensive disorder of pregnancy characterized by placental cell autophagy and death, remains unknown. Herein, we show that the mitochondrial dynamic balance in preeclamptic placentae is tilted toward fission (increased DRP1 expression/activation and decreased OPA1 expression). Increased phosphorylation of DRP1 (p-DRP1) in mitochondrial isolates from preeclamptic placentae and transmission electron microscopy corroborated augmented mitochondrial fragmentation in cytotrophoblast cells of PE placentae. Increased fission was accompanied by build-up of ceramides (CERs) in mitochondria from preeclamptic placentae relative to controls. Treatment of human choriocarcinoma JEG3 cells and primary isolated cytrophoblast cells with CER 16:0 enhanced mitochondrial fission. Loss- and gain-of-function experiments showed that Bcl-2 member BOK, whose expression is increased by CER, positively regulated p-DRP1/DRP1 and MFN2 expression, and localized mitochondrial fission events to the ER/MAM compartments. We also identified that the BH3 and transmembrane domains of BOK were vital for BOK regulation of fission. Moreover, we found that full-length PTEN-induced putative kinase 1 (PINK1) and Parkin, were elevated in mitochondria from PE placentae, implicating mitophagy as the process that degrades excess mitochondria fragments produced from CER/BOK-induced fission in preeclampsia. In summary, our study uncovered a novel CER/BOK-induced regulation of mitochondrial fission and its functional consequence for heightened trophoblast cell autophagy in preeclampsia.en
dc.description.affiliationLunenfeld-Tanenbaum Research Institute Sinai Health System
dc.description.affiliationInstitute of Medical Science University of Toronto
dc.description.affiliationDepartment of Obstetrics and Gynecology Botucatu Medical School UNESP - Sao Paulo State University
dc.description.affiliationDepartment of Physiology University of Toronto
dc.description.affiliationTranslational Medicine Program Peter Gilgan Center for Research and Learning Hospital for Sick Children
dc.description.affiliationDepartment of Obstetrics and Gynecology University of Toronto
dc.description.affiliationUnespDepartment of Obstetrics and Gynecology Botucatu Medical School UNESP - Sao Paulo State University
dc.description.sponsorshipNational Institutes of Health
dc.description.sponsorshipIdNational Institutes of Health: 1R01HD089660
dc.identifierhttp://dx.doi.org/10.1038/s41419-018-0360-0
dc.identifier.citationCell Death and Disease, v. 9, n. 3, 2018.
dc.identifier.doi10.1038/s41419-018-0360-0
dc.identifier.file2-s2.0-85042210051.pdf
dc.identifier.issn2041-4889
dc.identifier.scopus2-s2.0-85042210051
dc.identifier.urihttp://hdl.handle.net/11449/175906
dc.language.isoeng
dc.relation.ispartofCell Death and Disease
dc.relation.ispartofsjr2,536
dc.rights.accessRightsAcesso aberto
dc.sourceScopus
dc.titleCeramide-induced BOK promotes mitochondrial fission in preeclampsiaen
dc.typeArtigo
unesp.campusUniversidade Estadual Paulista (Unesp), Faculdade de Medicina, Botucatupt
unesp.departmentGinecologia e Obstetrícia - FMBpt

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