Dichotomy in hypoxia-induced mitochondrial fission in placental mesenchymal cells during development and preeclampsia: consequences for trophoblast mitochondrial homeostasis |
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| Authors: | Taylor Gillmore Abby Farrell Sruthi Alahari Julien Sallais Merve Kurt Chanho Park Jonathan Ausman Michael Litvack Martin Post Isabella Caniggia |
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| Affiliation: | 1.Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5T 3H7 Canada ;2.Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8 Canada ;3.Department of Physiology, University of Toronto, Toronto, ON M5S 1A8 Canada ;4.Translational Medicine Program, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G1X8 Canada ;5.Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON M5G 1E2 Canada |
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| Abstract: | Dynamic changes in physiologic oxygen are required for proper placenta development; yet, when low-oxygen levels persist, placental development is halted, culminating in preeclampsia (PE), a serious complication of pregnancy. Considering mitochondria’s function is intimately linked to oxygen changes, we investigated the impact of oxygen on mitochondrial dynamics in placental mesenchymal stromal cells (pMSCs) that are vital for proper placental development. Transmission electron microscopy, proximity ligation assays for mitochondrial VDAC1 and endoplasmic reticulum IP3R, and immunoanalyses of p-DRP1 and OPA1, demonstrate that low-oxygen conditions in early 1st trimester and PE promote mitochondrial fission in pMSCs. Increased mitochondrial fission of mesenchymal cells was confirmed in whole PE placental tissue sections. Inhibition of DRP1 oligomerization with MDiVi-1 shows that low oxygen-induced mitochondrial fission is a direct consequence of DRP1 activation, likely via HIF1. Mitophagy, a downstream event prompted by mitochondrial fission, is a prominent outcome in PE, but not 1st trimester pMSCs. We also investigated whether mesenchymal–epithelial interactions affect mitochondrial dynamics of trophoblasts in PE placentae. Exposure of trophoblastic JEG3 cells to exosomes of preeclamptic pMSCs caused heightened mitochondrial fission in the cells via a sphingomyelin-dependent mechanism that was restored by MDiVi-1. Our data uncovered dichotomous regulation of mitochondrial fission and health in human placental mesenchymal cells under physiologic and pathologic hypoxic conditions and its impact on neighboring trophoblast cells.Subject terms: Mechanisms of disease, Endocrine reproductive disorders |
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