Low chorionic villous succinate accumulation associates with recurrent spontaneous abortion risk

Nat Commun. 2021 Jun 8;12(1):3428. doi: 10.1038/s41467-021-23827-0.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abortion, Habitual / enzymology
  • Abortion, Habitual / genetics
  • Abortion, Habitual / metabolism*
  • Animals
  • Case-Control Studies
  • Cell Hypoxia
  • Cell Line, Tumor
  • Chorionic Villi / metabolism*
  • CpG Islands / genetics
  • DNA Methylation / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Expression Regulation
  • Glycolysis
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Metabolome
  • Mice
  • Mice, Inbred C57BL
  • Pregnancy
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Proto-Oncogene Proteins c-fos / metabolism
  • Risk Factors
  • Succinate Dehydrogenase / genetics
  • Succinate Dehydrogenase / metabolism
  • Succinic Acid / metabolism*
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Trophoblasts / metabolism
  • Trophoblasts / pathology

Substances

  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • MBD1 protein, human
  • Proto-Oncogene Proteins c-fos
  • Transcription Factors
  • Succinic Acid
  • SDHB protein, human
  • Succinate Dehydrogenase