Zhang Junqiang, Yu Hui, Fan Yongqi, Wu Longmei, Fang Yuan, Wei Zhaolian, Zhang Zhiguo, Cao Yunxia
Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People's Republic of China, Hefei 230032, China.
Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei 230032, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei 230032, China.
Reprod Biol. 2024 Dec;24(4):100954. doi: 10.1016/j.repbio.2024.100954. Epub 2024 Sep 21.
The integrated stress response (ISR) is implicated in age-related diseases, while the molecular chaperone heat shock protein 70 (HSP70) can facilitate proper protein folding. However, the regulatory mechanism of ISR in insufficient testosterone synthesis of aging Leydig cells (LCs) remains unclear. This study aims to elucidate the regulatory role of ISR in inadequate testosterone synthesis of aging LCs. We observed a positive correlation between testosterone and HSP70 levels, which were found to be decreased in elderly men. ISR was detected in testicular tissue from old mice. The expression of testosterone synthesis related protein and the content of testosterone decreased in testicular tissue of old mice. Conversely, inhibition of the integrated stress response in testicular tissue led to an increase in steroid synthase expression among old mice. Furthermore, inhibiting ISR specifically within aging LCs resulted in enhanced protein translation efficiency and increased expression levels of new HSP70 and steroidogenic acute regulatory protein (StAR). These findings suggest that ISR occurrence within aging LCs affects StAR protein expression through regulation of HSP70-mediated translation, consequently impairing testosterone synthesis.
整合应激反应（ISR）与年龄相关疾病有关，而分子伴侣热休克蛋白70（HSP70）可促进蛋白质正确折叠。然而，ISR在衰老的睾丸间质细胞（LCs）睾酮合成不足中的调节机制仍不清楚。本研究旨在阐明ISR在衰老LCs睾酮合成不足中的调节作用。我们观察到睾酮与HSP70水平呈正相关，且在老年男性中发现二者水平均降低。在老年小鼠的睾丸组织中检测到了ISR。老年小鼠睾丸组织中睾酮合成相关蛋白表达及睾酮含量降低。相反，抑制老年小鼠睾丸组织中的整合应激反应会导致类固醇合成酶表达增加。此外，特异性抑制衰老LCs内的ISR会提高蛋白质翻译效率，并增加新的HSP70和类固醇生成急性调节蛋白（StAR）的表达水平。这些发现表明，衰老LCs内发生的ISR通过调节HSP70介导的翻译影响StAR蛋白表达，从而损害睾酮合成。
