Dichotomy in hypoxia-induced mitochondrial fission in placental mesenchymal cells during development and preeclampsia: consequences for trophoblast mitochondrial homeostasis

Taylor Gillmore,Sruthi Alahari,Michael Litvack,Jonathan Ausman,Martin Post,Julien Sallais,Abby Farrell,Chanho Park,Merve Kurt,Isabella Caniggia

doi:10.1038/s41419-022-04641-y

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.

Highlights

Mitochondria are critical organelles responsible for cell survival and death [1, 2]
Mitochondrial fission is orchestrated by dynamin-related protein 1 (DRP1), a cytosolic protein that is recruited to the outer mitochondrial membrane (OMM) to induce mitochondrial division through a GTP-dependent conformational change [6]
Mitochondrial fission is increased in placental mesenchymal stromal cells (pMSCs) isolated from early 1st trimester placenta We first examined mitochondrial dynamic events in pMSCs isolated from placentae across the 1st trimester of gestation

Summary

Introduction

Mitochondria are critical organelles responsible for cell survival and death [1, 2]. Importantly, not all mitochondria “are created equal”, and changes in their morphology is a central determinant of their capacity to generate essential ATP or to produce harmful byproducts, such as reactive oxygen species (ROS) [3]. Compared to mitochondria from 10 to 12-week pMSCs, Fig. 4 Placental mesenchymal stromal cells isolated from preeclamptic (PE) placentae exhibit increased mitochondrial fission.

Results

Conclusion