Knockout of Peroxiredoxin 4 Disrupts Spermatogenesis Due to Oxidative Stress and Endoplasmic Reticulum Stress

Abstract

BackgroundThe main functions of testes are the sperm production and androgen secretion in testicular befitting microenvironment. Excessive level of the reactive oxygen species (ROS) from metabolism and cellular events can lead to oxidative stress (OS) and ER stress, which injure the functions of mitochondria and ER of testicular cells, leading to the impaired spermatogenesis and spermiogenesis, as well as insufficient androgen. Our previous studies have showed that peroxiredoxin 4 (Prdx4) is a vital ER-located protector against ER stress in ovarian granulosa cells. In this study, we explored whether Prdx4 played a beneficial role in testes, and the potential application value in male reproduction.MethodsPrdx4 knockout mice were established using CRISPR/Cas9 system, and male Prdx4−/y mice were disposed at the 9-week and 9-month stages. The natural adult (9 weeks) and aging (9 months) mice were used as control. To further investigate the protective effect of Prdx4 in the adult mice, the testicular 43°C-water bath to induce a heat stress was used as the OS model.ResultsThe male Prdx4−/y mice aged over 9-months showed the age-related pathology of seminiferous tubule, the increased OS and ER stress and the decreased fertility. The adult Prdx4−/y mice under heat stress manifested the increased levels of OS and ER stress, higher ferroptosis and mitochondrial autophagy, and poorer fertility.ConclusionWe concluded that Prdx4 as a protective factor plays a critical role in preserving spermatogenesis by alleviating testicular ER stress and OS, and that Prdx4 may be known as a potential target in mitigating the adverse effects of natural aging and OS injury.

Note:
Funding declaration: This study was supported by grants from the National Nature and Science Foundation of China (82171593, 82271638) and Innovation Center of Reproductive Medicine in Jiangsu Province of China (CXZX202207).

Conflict of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical Approval: The design and protocol of animal experiments were approved by the Animal Care Committee of Nanjing Medical University (IACUC-2307053).

Keywords: Peroxiredoxin 4, Oxidative stress, Endoplasmic reticulum stress, Male reproductive aging