Dichotomy in hypoxia-induced mitochondrial fission in placental mesenchymal cells during development and preeclampsia: consequences for trophoblast mitochondrial homeostasis.
Dichotomy in hypoxia-induced mitochondrial fission in placental mesenchymal cells during development and preeclampsia: consequences for trophoblast mitochondrial homeostasis.
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DOI：
10.1038/s41419-022-04641-y
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发表时间：
2022-02-26
影响因子：
9
通讯作者：
Caniggia I
中科院分区：
文献类型：
--
作者：
Gillmore T;Farrell A;Alahari S;Sallais J;Kurt M;Park C;Ausman J;Litvack M;Post M;Caniggia I
生理氧的动态变化是胎盘正常发育所必需的;然而，当低氧水平持续时，胎盘发育停止，最终导致先兆子痫（PE），这是一种严重的妊娠并发症。考虑到线粒体的功能与氧的变化密切相关，我们研究了氧对胎盘间充质基质细胞（pMSCs）中线粒体动力学的影响，这些细胞对胎盘的正常发育至关重要。透射电子显微镜、线粒体VDAC 1和内质网IP 3R的邻近连接测定以及p-DRP 1和OPA 1的免疫分析表明，妊娠早期低氧条件和PE促进pMSC中的线粒体分裂。在整个PE胎盘组织切片中证实了间充质细胞的线粒体分裂增加。用MDiVi-1抑制DRP 1寡聚化表明低氧诱导的线粒体分裂是DRP 1激活的直接结果，可能通过HIF 1。线粒体自噬是由线粒体分裂引起的下游事件，是PE中的一个突出结果，但不是妊娠早期pMSC。我们还研究了间充质-上皮相互作用是否影响PE胎盘滋养层细胞的线粒体动力学。将滋养层JEG 3细胞暴露于先兆子痫pMSC的外泌体通过鞘磷脂依赖性机制引起细胞中线粒体分裂增加，该机制由MDiVi-1恢复。我们的数据揭示了在生理和病理缺氧条件下，人胎盘间充质细胞线粒体分裂和健康的二分调节及其对邻近滋养层细胞的影响。
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.
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影响因子：
7
作者：
Hoque A;Sivakumaran P;Bond ST;Ling NXY;Kong AM;Scott JW;Bandara N;Hernández D;Liu GS;Wong RCB;Ryan MT;Hausenloy DJ;Kemp BE;Oakhill JS;Drew BG;Pébay A;Lim SY
通讯作者：
Lim SY
影响因子：
13.3
作者：
Melland-Smith, Megan;Ermini, Leonardo;Caniggia, Isabella
通讯作者：
Caniggia, Isabella
影响因子：
8
作者：
Farrell, Abby;Alahari, Sruthi;Caniggia, Isabella
通讯作者：
Caniggia, Isabella
影响因子：
6.5
作者：
Justice, Matthew J.;Bronova, Irina;Petrache, Irina
通讯作者：
Petrache, Irina
影响因子：
5.2
作者：
Chang CR;Blackstone C
通讯作者：
Blackstone C