Mitochondrial fusion protein 2 regulates endoplasmic reticulum stress in preeclampsia

线粒体融合蛋白 2 (Mfn2) 调节内质网应激在子痫前期的作用及其机制研究

概要

目的

探究线粒体融合蛋白 2 (Mfn2) 调控的内质网应激在子痫前期发生中的作用机制, 为临床子痫前期的诊断和治疗提供参考.

创新点

本论文着眼于滋养层细胞的内质网应激在子痫前期中具有重要作用这一研究热点, 通过对临床样本的检测和细胞水平的研究, 阐明了 Mfn2 调控的内质网应激在子痫前期发生中的重要作用, 初步确定该基因可能作为子痫前期的诊断和治疗靶点. 该研究具有针对性强、 创新高以及满足现实发展需求的意义.

方法

采用蛋白质免疫印迹法检测子痫前期和正常胎盘组织中 Mfn2 的表达差异; 活细胞计数 (CCK8) 法、 细胞划痕、 Transwell、 流式细胞术等实验方法分别用于检测 Mfn2 敲低对滋养层细胞 JEG-3 增殖、 迁移、 侵袭和凋亡的影响. 蛋白质免疫印迹法检测内质网应激条件下滋养层细胞中 Mfn2 的表达, 并通过 CCK8、 流式细胞术和超氧化物歧化酶 (SOD) 的测定检测 Mfn2 过表达后对内质网应激条件下滋养层细胞的细胞活力和氧化应激的改善情况.

结论

Mfn2 在子痫前期胎盘组织中低表达, 下调 Mfn2 可显著抑制滋养层细胞的增殖、 迁移和侵袭. 子痫前期下内质网应激将抑制 Mfn2 的表达, Mfn2 的稳定表达可以通过调节内质网应激抑制子痫前期发生和发展.

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References

  1. Brosens I, Brosens JJ, Muter J, et al., 2019. Preeclampsia: the role of persistent endothelial cells in uteroplacental arteries. Am J Obstet Gynecol, 221(3):219–226. https://doi.org/10.1016/j.ajog.2019.01.239

    CAS  Article  Google Scholar 

  2. Burton GJ, Jauniaux E, Charnock-Jones DS, 2010. The influence of the intrauterine environment on human placental development. Int J Dev Biol, 54(2–3):303–311. https://doi.org/10.1387/ijdb.082764gb

    CAS  Article  Google Scholar 

  3. Chaiworapongsa T, Chaemsaithong P, Yeo L, et al., 2014. Preeclampsia part 1: current understanding of its pathophysiology. Nat Rev Nephrol, 10(8):466–480. https://doi.org/10.1038/nrneph.2014.102

    CAS  Article  Google Scholar 

  4. Chan DC, 2006. Mitochondrial fusion and fission in mammals. Annu Rev Cell Dev Biol, 22:79–99. https://doi.org/10.1146/annurev.cellbio.22.010305.104638

    CAS  Article  Google Scholar 

  5. Chandhok G, Lazarou M, Neumann B, 2018. Structure, function, and regulation of mitofusin-2 in health and disease. Biol Rev Camb Philos Soc, 93(2):933–949. https://doi.org/10.1111/brv.12378

    Article  Google Scholar 

  6. Debattisti V, Pendin D, Ziviani E, et al., 2014. Reduction of endoplasmic reticulum stress attenuates the defects caused by Drosophila mitofusin depletion. J Cell Biol, 204(3):303–312. https://doi.org/10.1083/jcb.201306121

    CAS  Article  Google Scholar 

  7. Du L, He F, Kuang L, et al., 2017. eNOS/iNOS and endoplasmic reticulum stress-induced apoptosis in the placentas of patients with preeclampsia. J Hum Hypertens, 31(1):49–55. https://doi.org/10.1038/jhh.2016.17

    CAS  Article  Google Scholar 

  8. Eddy AC, Chapman H, George EM, 2019. Acute hypoxia and chronic ischemia induce differential total changes in placental epigenetic modifications. Reprod Sci, 26(6):766–773. https://doi.org/10.1177/1933719118799193

    CAS  Article  Google Scholar 

  9. Genbacev O, Miller RK, 2000. Post-implantation differentiation and proliferation of cytotrophoblast cells: in vitro models—a review. Placenta, 21(Suppl A):S45–S49. https://doi.org/10.1053/plac.1999.0523

    Article  Google Scholar 

  10. Lorenzon-Ojea AR, Yung HW, Burton GJ, et al., 2020. The potential contribution of stromal cell-derived factor 2 (SDF2) in endoplasmic reticulum stress response in severe preeclampsia and labor-onset. Biochim Biophys Acta-Mol Basis Dis, 1866(2):165386. https://doi.org/10.1016/j.bbadis.2019.01.012

    CAS  Article  Google Scholar 

  11. Muñoz JP, Ivanova S, Sánchez-Wandelmer J, et al., 2013. Mfn2 modulates the UPR and mitochondrial function via repression of PERK. EMBO J, 32(17):2348–2361. https://doi.org/10.1038/emboj.2013.168

    Article  Google Scholar 

  12. Ngoh GA, Papanicolaou KN, Walsh K, 2012. Loss of mitofusin 2 promotes endoplasmic reticulum stress. J Biol Chem, 287(24):20321–20332. https://doi.org/10.1074/jbc.M112.359174

    CAS  Article  Google Scholar 

  13. Schneeberger M, Dietrich MO, Sebastián D, et al., 2013. Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell, 155(1):172–187. https://doi.org/10.1016/j.cell.2013.09.003

    CAS  Article  Google Scholar 

  14. Song MS, Mihara K, Chen Y, et al., 2015. Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts. Cell Metab, 21(2):273–286. https://doi.org/10.1016/j.cmet.2014.12.011

    CAS  Article  Google Scholar 

  15. Steegers EAP, von Dadelszen P, Duvekot JJ, et al., 2010. Preeclampsia. Lancet, 376(9741):631–644. https://doi.org/10.1016/S0140-6736(10)60279-6

    Article  Google Scholar 

  16. Yu J, Guo XJ, Chen RB, et al., 2016. Downregulation of mitofusin 2 in placenta is related to preeclampsia. Biomed Res Int, 2016:6323086. https://doi.org/10.1155/2016/6323086

    PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by the Welfare Technology-Applied Research Project of Zhejiang Province (No. LGF20H 040011), China.

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Authors

Contributions

Jihua JIN conceived the study and reviewed the manuscript. Dandan SUN searched the literature, collected the data, and drafted the manuscript. Hanbing WU, Ling AI, Yanting WU, and Hui ZHU performed the statistical analysis. All authors have read and approved the final paper, and they have full access to all the data in the study and take responsibility for the integrity and security of the data.

Corresponding author

Correspondence to Jihua Jin.

Ethics declarations

Dandan SUN, Hui ZHU, Ling AI, Hanbing WU, Yanting WU, and Jihua JIN declare that they have no conflict of interest.

The present study was approved by the Ethics Committee of Jiaxing Municipal Maternal and Child Health Care Hospital (Jiaxing, China). All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study. Additional informed consent was obtained from all patients for whom identifying information is included in this article.

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Sun, D., Zhu, H., Ai, L. et al. Mitochondrial fusion protein 2 regulates endoplasmic reticulum stress in preeclampsia. J. Zhejiang Univ. Sci. B 22, 165–170 (2021). https://doi.org/10.1631/jzus.B2000557

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关键词

  • 线粒体融合蛋白 2 (Mfn2)
  • 内质网应激
  • 子痫前期