Abnormal early folliculogenesis due to impeded pyruvate metabolism in mouse oocytes

Keiko Tanaka, Yohei Hayashi, Asuka Takehara, Yumi Ito-Matsuoka, Masahito Tachibana, Nobuo Yaegashi, Yasuhisa Matsui

Research output: Contribution to journalArticlepeer-review

Abstract

Fetal ovarian germ cells show characteristic energy metabolism status, such as enhanced mitochondrial metabolism as well as glycolysis, but their roles in early folliculogenesis are unclear. We show here that inhibition of pyruvate uptake to mitochondria by UK5099 in organ cultures of fetal mouse ovaries resulted in repressed early folliculogenesis without affecting energy production, survival of oocytes, or meiosis. In addition, the abnormal folliculogenesis by UK5099 was partially rescued by α-ketoglutarate and succinate, intermediate metabolites in the TCA cycle, suggesting the importance of those metabolites. The expression of TGFβ-related genes Gdf9 and Bmp15 in ovarian germ cells, which are crucial for folliculogenesis, was downregulated by UK5099, and the addition of recombinant GDF9 partially rescued the abnormal folliculogenesis induced by UK5099. We also found that early folliculogenesis was similarly repressed, as in the culture, in the ovaries of a germ cell-specific knockout of Mpc2, which encodes a mitochondria pyruvate carrier that is targeted by UK5099. These results suggest that insufficient Gdf9 expression induced by abnormal pyruvate metabolism in oocytes results in early follicular dysgenesis, which is a possible cause of defective folliculogenesis in humans.

Original languageEnglish
Pages (from-to)64-75
Number of pages12
JournalBiology of Reproduction
Volume105
Issue number1
DOIs
Publication statusPublished - 2021 Jul 1

Keywords

  • Folliculogenesis
  • GDF9
  • Glycolysis
  • MPC
  • Oocyte
  • OXPHOS
  • Pyruvate metabolism
  • UK5099

ASJC Scopus subject areas

  • Reproductive Medicine
  • Cell Biology

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