Abnormal mitochondrial function and impaired granulosa cell differentiation in androgen receptor knockout mice.
In the ovary, the paracrine interactions between the oocyte and surrounded granulosa cells are critical for optimal oocyte quality and embryonic development. Mice lacking the androgen receptor (AR⁻/⁻) were noted to have reduced fertility with abnormal ovarian function that might involve the promotion of preantral follicle growth and prevention of follicular atresia. However, the detailed mechanism of how AR in granulosa cells exerts its effects on oocyte quality is poorly understood. Comparing in vitro maturation rate of oocytes, we found oocytes collected from AR⁻/⁻ mice have a significantly poor maturating rate with 60% reached metaphase II and 30% remained in germinal vesicle breakdown stage, whereas 95% of wild-type AR (AR⁺/⁺) oocytes had reached metaphase II. Interestingly, we found these AR⁻/⁻ female mice also had an increased frequency of morphological alterations in the mitochondria of granulosa cells with reduced ATP generation (0.18 ± 0.02 vs. 0.29 ± 0.02 µM/mg protein; p < 0.05) and aberrant mitochondrial biogenesis. Mechanism dissection found loss of AR led to a significant decrease in the expression of peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1-β (PGC1-β) and its sequential downstream genes, nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), in controlling mitochondrial biogenesis. These results indicate that AR may contribute to maintain oocyte quality and fertility via controlling the signals of PGC1-β-mediated mitochondrial biogenesis in granulosa cells.
Graduate Institute of Clinical Medicine & Department of Obstetrics and Gynecology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. d102094001@tmu.edu.tw.
Ruey-Sheng
RS
Wang
Department of Biochemistry and Molecular Cell Biology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. hychang@tmu.edu.tw.
Heng-Yu
HY
Chang
School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan. kaosh@tmu.edu.tw.
Shu-Huei
SH
Kao
Center of General Education, Chang Gung University, Taoyuan 333, Taiwan. kao@mail.cgu.edu.tw.
Cheng-Heng
CH
Kao
Graduate Institute of Clinical Medicine & Department of Obstetrics and Gynecology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. vvichern@yahoo.com.tw.
Yi-Chen
YC
Wu
George H. Whipple Lab for Cancer Research, Departments of Pathology, Urology and Radiation Oncology, University of Rochester Medical Center, Rochester, NY 14642, USA. shuyuan_yeh@urmc.rochester.edu.
Shuyuan
S
Yeh
Graduate Institute of Clinical Medicine & Department of Obstetrics and Gynecology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. tzengcr@tmu.edu.tw.
Chii-Reuy
CR
Tzeng
George H. Whipple Lab for Cancer Research, Departments of Pathology, Urology and Radiation Oncology, University of Rochester Medical Center, Rochester, NY 14642, USA. chang@urmc.rochester.edu.
Chawnshang
C
Chang
D000818:Animals; D002454:Cell Differentiation; D048430:Cell Shape; D004958:Estradiol / Q000097:blood; D005260:Female; D005838:Genotype; D006107:Granulosa Cells / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D059471:In Vitro Oocyte Maturation Techniques; D053078:Membrane Potential, Mitochondrial; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D009865:Oocytes / Q000378:metabolism; D001678:Organelle Biogenesis; D011944:Receptors, Androgen / Q000172:deficiency* / Q000378:metabolism; D015203:Reproducibility of Results
D011944:Receptors, Androgen; D004958:Estradiol