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

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

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bb43093b4ce64961bbdd8841d065f5afTest
http://hdl.handle.net/11365/1095267Test

المؤلفون: Liane Jennifer Bailey, Sruthi Alahari, Andrea Tagliaferro, Martin Post, Isabella Caniggia

المصدر: Cell Death & Disease

مصطلحات موضوعية: 0301 basic medicine, Cancer Research, Programmed cell death, medicine.medical_specialty, Ceramide, Indoles, Necroptosis, Placenta, Immunology, Cell, Apoptosis, Biology, Ceramides, Amino Acid Chloromethyl Ketones, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Necrosis, Pre-Eclampsia, Pregnancy, Internal medicine, Cell Line, Tumor, medicine, Humans, Phosphorylation, reproductive and urinary physiology, Caspase 8, Cytotrophoblast, Cell Death, Autophagy, Imidazoles, Trophoblast, Cell Biology, Cadherins, 3. Good health, Cell biology, Trophoblasts, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, chemistry, embryonic structures, Quinolines, Female, Original Article, Neuroglia, Protein Kinases, Signal Transduction

الوصف: Preeclampsia, a serious hypertensive disorder of pregnancy, is characterized by elevated ceramide (CER) content that is responsible for heightened trophoblast cell death rates via apoptosis and autophagy. Whether trophoblast cells undergo necroptosis, a newly characterized form of regulated necrosis, and the potential role of CER in this process remain to be established. Herein, we report that exposure of both JEG3 cells and primary isolated cytotrophoblasts to C16:0 CER in conjunction with a caspase-8 inhibitor (Q-VD-OPh) promoted necroptotic cell death, as evidenced by increased expression and association of receptor-interacting protein kinases RIP1 and RIP3, as well as phosphorylation of mixed lineage kinase domain-like (MLKL) protein. MLKL activation and oligomerization could be abrogated by pretreatment with the necroptosis inhibitor necrostatin-1 (Nec-1). CER+Q-VD-OPH-treated primary trophoblasts displayed striking necrotic morphology along with disrupted fusion processes as evidenced by maintenance of E-cadherin-stained membrane boundaries and reduced glial cell missing-1 expression, but these events were effectively reversed using Nec-1. Of clinical relevance, we established an increased susceptibility to necroptotic cell death in preeclamptic placentae relative to normotensive controls. In preeclampsia, increased necrosome (RIP1/RIP3) protein levels, as well as MLKL activation and oligomerization associated with necrotic cytotrophoblast morphology. In addition, caspase-8 activity was reduced in severe early-onset preeclampsia cases. This study is the first to report that trophoblast cells undergo CER-induced necroptotic cell death, thereby contributing to the increased placental dysfunction and cell death found in preeclampsia.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1a73a14372c3f0cce3401f324d4590d9Test
https://pubmed.ncbi.nlm.nih.gov/28151467Test