Ceramide-induced BOK promotes mitochondrial fission in preeclampsia
| العنوان: | Ceramide-induced BOK promotes mitochondrial fission in preeclampsia |
|---|---|
| المؤلفون: | Isabella Caniggia, Abby Farrell, Jonathan Ausman, Andrea Tagliaferro, Joelcio Francisco Abbade, Martin Post, Leonardo Ermini |
| المساهمون: | Sinai Health System, University of Toronto, Universidade Estadual Paulista (Unesp), Hospital for Sick Children |
| المصدر: | Cell Death and Disease, Vol 9, Iss 3, Pp 1-18 (2018) Scopus Repositório Institucional da UNESP Universidade Estadual Paulista (UNESP) instacron:UNESP Cell Death & Disease |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Adult, Dynamins, Male, Cancer Research, Ceramide, Placenta, Immunology, MFN2, PINK1, Mitochondrion, Ceramides, Mitochondrial Dynamics, Article, GTP Phosphohydrolases, Mitochondrial Proteins, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Mice, Young Adult, Pre-Eclampsia, Protein Domains, Pregnancy, Mitophagy, medicine, Animals, Autophagy, Female, Humans, Microtubule-Associated Proteins, Mitochondria, Phosphorylation, Proto-Oncogene Proteins c-bcl-2, lcsh:QH573-671, Cytotrophoblast, Chemistry, lcsh:Cytology, Cell Biology, 3. Good health, Cell biology, 030104 developmental biology, medicine.anatomical_structure, embryonic structures, Mitochondrial fission |
| الوصف: | Made available in DSpace on 2018-12-11T17:18:04Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-03-01 National Institutes of Health Mitochondria 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. Lunenfeld-Tanenbaum Research Institute Sinai Health System Institute of Medical Science University of Toronto Department of Obstetrics and Gynecology Botucatu Medical School UNESP - Sao Paulo State University Department of Physiology University of Toronto Translational Medicine Program Peter Gilgan Center for Research and Learning Hospital for Sick Children Department of Obstetrics and Gynecology University of Toronto Department of Obstetrics and Gynecology Botucatu Medical School UNESP - Sao Paulo State University National Institutes of Health: 1R01HD089660 |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bb43093b4ce64961bbdd8841d065f5afTest http://hdl.handle.net/11365/1095267Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....bb43093b4ce64961bbdd8841d065f5af |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |