TY - JOUR
T1 - Abnormal early folliculogenesis due to impeded pyruvate metabolism in mouse oocytes
AU - Tanaka, Keiko
AU - Hayashi, Yohei
AU - Takehara, Asuka
AU - Ito-Matsuoka, Yumi
AU - Tachibana, Masahito
AU - Yaegashi, Nobuo
AU - Matsui, Yasuhisa
N1 - Funding Information:
Grant Support: For part of this work, YM was supported by Grant-in-Aid for Scientific Research (KAKENHI) (B) (grant 19H03231) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT). YH was supported by Grant-in-Aid for Scientific Research (KAKENHI) (C) (grant 19K06434) and KAKENHI in the Innovative Areas, “Sex Spectrum” (grant 18H04875) and “Ensuring integrity in gametogenesis” (grant 19H05238) from MEXT, and by Takeda Science Foundation, Kato Memorial Bioscience Foundation, the Inamori Foundation, and Astellas Foundation for Research on Metabolic Disorders.
Publisher Copyright:
© The Author(s) 2021. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - 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.
AB - 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.
KW - Folliculogenesis
KW - GDF9
KW - Glycolysis
KW - MPC
KW - OXPHOS
KW - Oocyte
KW - Pyruvate metabolism
KW - UK5099
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U2 - 10.1093/biolre/ioab064
DO - 10.1093/biolre/ioab064
M3 - Article
C2 - 33824958
AN - SCOPUS:85109537810
VL - 105
SP - 64
EP - 75
JO - Biology of Reproduction
JF - Biology of Reproduction
SN - 0006-3363
IS - 1
ER -