Mitochondrial deoxyguanosine kinase is required for female fertility in mice

Mitochondrial homeostasis plays a pivotal role in oocyte maturation and embryonic development. Deoxyguanosine kinase (DGUOK) is a nucleoside kinase that salvages purine nucleosides in mitochondria and is critical for mitochondrial DNA replication and homeostasis in non-proliferating cells. loss-of-f...

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Published in:Acta biochimica et biophysica Sinica 2024-02, Vol.56 (3), p.427-439
Main Authors: Gao, Yake, Dong, Rui, Yan, Jiacong, Chen, Huicheng, Sang, Lei, Yao, Xinyi, Fan, Die, Wang, Xin, Zuo, Xiaoyuan, Zhang, Xu, Yang, Shengyu, Wu, Ze, Sun, Jianwei
Format: Article
Language:English
Subjects:
Animals
DGUOK
DNA, Mitochondrial - genetics
DNA, Mitochondrial - metabolism
Female
Fertility - genetics
Humans
infertility
Infertility, Female - genetics
Mice
mitochondria
Mitochondria - genetics
Mitochondria - metabolism
Mitochondrial Diseases
nucleoside salvage pathway
oocyte maturation
Oocytes - metabolism
Phosphotransferases (Alcohol Group Acceptor)
Pregnancy
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Summary:Mitochondrial homeostasis plays a pivotal role in oocyte maturation and embryonic development. Deoxyguanosine kinase (DGUOK) is a nucleoside kinase that salvages purine nucleosides in mitochondria and is critical for mitochondrial DNA replication and homeostasis in non-proliferating cells. loss-of-function mutations and deletions lead to hepatocerebral mitochondrial DNA deletion syndrome. However, its potential role in reproduction remains largely unknown. In this study, we find that knockout results in female infertility. Mechanistically, DGUOK deficiency hinders ovarian development and oocyte maturation. Moreover, DGUOK deficiency in oocytes causes a significant reduction in mitochondrial DNA copy number and abnormal mitochondrial dynamics and impairs germinal vesicle breakdown. Only few DGUOK-deficient oocytes can extrude their first polar body during maturation, and these oocytes exhibit irregular chromosome arrangements and different spindle lengths. In addition, DGUOK deficiency elevates reactive oxygen species levels and accelerates oocyte apoptosis. Our findings reveal novel physiological roles for the mitochondrial nucleoside salvage pathway in oocyte maturation and implicate DGUOK as a potential marker for the diagnosis of female infertility.
ISSN:1672-9145
1745-7270
DOI:10.3724/abbs.2024003