Low chorionic villous succinate accumulation associates with recurrent spontaneous abortion risk

Xiao-Hui Wang, Sha Xu, Xiang-Yu Zhou, Rui Zhao, Yan Lin, Jing Cao, Wei-Dong Zang, Hui Tao, Wei Xu, Ming-Qing Li, Shi-Min Zhao, Li-Ping Jin () and Jian-Yuan Zhao ()
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Xiao-Hui Wang: Tongji University School of Medicine
Sha Xu: Fudan University
Xiang-Yu Zhou: Tongji University School of Medicine
Rui Zhao: Fudan University
Yan Lin: Fudan University
Jing Cao: Zhengzhou University
Wei-Dong Zang: Zhengzhou University
Hui Tao: Anhui Medical University
Wei Xu: Fudan University
Ming-Qing Li: Fudan University
Shi-Min Zhao: Fudan University
Li-Ping Jin: Tongji University School of Medicine
Jian-Yuan Zhao: Tongji University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Dysregulated extravillous trophoblast invasion and proliferation are known to increase the risk of recurrent spontaneous abortion (RSA); however, the underlying mechanism remains unclear. Herein, in our retrospective observational case-control study we show that villous samples from RSA patients, compared to healthy controls, display reduced succinate dehydrogenase complex iron sulfur subunit (SDHB) DNA methylation, elevated SDHB expression, and reduced succinate levels, indicating that low succinate levels correlate with RSA. Moreover, we find high succinate levels in early pregnant women are correlated with successful embryo implantation. SDHB promoter methylation recruited MBD1 and excluded c-Fos, inactivating SDHB expression and causing intracellular succinate accumulation which mimicked hypoxia in extravillous trophoblasts cell lines JEG3 and HTR8 via the PHD2-VHL-HIF-1α pathway; however, low succinate levels reversed this effect and increased the risk of abortion in mouse model. This study reveals that abnormal metabolite levels inhibit extravillous trophoblast function and highlights an approach for RSA intervention.

Date: 2021
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DOI: 10.1038/s41467-021-23827-0

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