Abstract
Mitochondrial dysfunction plays a crucial role in the pathological physiology of polycystic ovary syndrome (PCOS). Mitochondrial quality control system is vital to maintaining mitochondrial function, includes mitochondrial biosynthesis, dynamics and mitophagy. While mitophagy as a specific autophagy, plays an important role in the mitochondrial quality control system and is mediated by some signaling pathways to eliminate the excessive production of reactive oxygen species (ROS), such as hypoxia-inducible factor (HIF)-1α/B-cell lymphoma-2 adenovirus E1B 19 kDa interacting protein 3 (BNIP3). Our previous studies have found that excessive production of ROS and the decreased expression of HIF-1α in the ovaries of PCOS rats. Thus, we hypothesized that excessive ROS leads to mitochondrial dysfunction, attenuates HIF-1α/BNIP3-mediated mitophagy in the ovaries of PCOS rats, and further reduces the mitophagic defense. Firstly, the oxidative stress status was detected and found excessive ROS damages ovarian tissue in PCOS rats. Secondly, the marker proteins of mitochondrial biosynthesis/dynamics and amount were examined and found that their expression levels were abnormal, which showed that the abnormal mitochondrial quality control system leads to accumulate the excess or damaged mitochondria in PCOS ovaries. Finally, we detected the HIF-1α/BNIP3 pathway and found HIF-1α-mediated mitophagy is impaired in the ovaries of PCOS rats. Together, these results clearly demonstrated excessive ROS causes mitochondrial dysfunction via the abnormal mitochondrial quality control system, and attenuates HIF-1α/BNIP3-mediated mitophagic defense in the granulosa cells of PCOS rats, which will provide a new direction for further understanding the role of HIF-1α in the molecular mechanism of mitochondrial dysfunction in PCOS ovaries.
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Data that support the findings of this study are available from the corresponding author upon reasonable request.
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Funding
This research was funded by the Key Projects of Scientific and Technological Innovation in Fujian Province (Grant Nos. 2021G02021 and 2021G02023), Special Funds of the Central Government Guilding Local Science and Technology Development (2020L3008), Fujian Provincial Natural Science Foundation (2019R1011-3 and 2020J01176), and Scientific Research Talent Project of Fujian Provincial Health Commission (2018-ZQN-20).
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FW and YL: designed the experiment. JH and XW: performed the experiment. FW: wrote the manuscript. FW: analyzed the data. ZZ: revised the manuscript.
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Wang, F., Han, J., Wang, X. et al. Roles of HIF-1α/BNIP3 mediated mitophagy in mitochondrial dysfunction of letrozole-induced PCOS rats. J Mol Histol 53, 833–842 (2022). https://doi.org/10.1007/s10735-022-10096-4
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DOI: https://doi.org/10.1007/s10735-022-10096-4