Lv Yinghua, Li Tianjiao, Yang Manman, Su Lihong, Zhu Zhendong, Zhao Sihang, Zeng Wenxian, Zheng Yi
Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, China.
Key Laboratory for Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China.
Front Cell Dev Biol. 2021 Jun 4;9:684398. doi: 10.3389/fcell.2021.684398. eCollection 2021.
Spermatogonial stem cells (SSCs) are the basis of spermatogenesis, and any damage to SSCs may result in spermatogenic disorder and male infertility. Chromium (Cr) (VI) is a proven toxin, mutagen, and carcinogen, perpetually detrimental to environmental organisms due to its intricate and enduring detoxification process . Despite this, the deleterious effects of Cr (VI) on SSCs and the underlying mechanisms remain poorly understood. In this study, we identified that Cr (VI) impaired male reproductive system in mouse testes and induced mitochondrial dynamic imbalance and mitophagy in SSCs/progenitors. Cr (VI) also downregulated the RNA N-methyladenosine (mA) modification levels in mitochondrial dynamic balance and mitophagy genes in SSCs/progenitors. Inspiringly, the toxic effects of Cr (VI) could be relieved by melatonin pretreatment. Melatonin alleviated Cr (VI)-induced damage to male reproductive system and autophagy in mouse testes. Melatonin also attenuated Cr (VI)-induced cell viability loss and reactive oxygen species (ROS) generation, as well as mitochondrial dynamic disorders and mitophagy in SSCs/progenitors. The protective roles of melatonin against Cr (VI)-induced mitophagy were exerted by restoration of METTL3-mediated RNA mA modification and activation of mitochondrial fusion proteins MFN2 and OPA1, as well as inhibition of the mitophagy BNIP3/NIX receptor pathway. Thus, our study provides novel insights into the molecular mechanisms for RNA mA modification underlying the gene regulatory network responsible for mitochondrial dynamic balance, and also lays new experimental groundwork for treatment of Cr (VI)-induced damage to male fertility.
精原干细胞（SSCs）是精子发生的基础，对SSCs的任何损伤都可能导致生精障碍和男性不育。六价铬（Cr）（VI）是一种已被证实的毒素、诱变剂和致癌物，由于其复杂且持久的解毒过程，对环境生物一直有害。尽管如此，Cr（VI）对SSCs的有害影响及其潜在机制仍知之甚少。在本研究中，我们发现Cr（VI）损害了小鼠睾丸中的雄性生殖系统，并诱导了SSCs/祖细胞中的线粒体动力学失衡和线粒体自噬。Cr（VI）还下调了SSCs/祖细胞中线粒体动力学平衡和线粒体自噬基因的RNA N-甲基腺苷（mA）修饰水平。令人鼓舞的是，褪黑素预处理可以减轻Cr（VI）的毒性作用。褪黑素减轻了Cr（VI）诱导的小鼠睾丸雄性生殖系统损伤和自噬。褪黑素还减弱了Cr（VI）诱导的细胞活力丧失和活性氧（ROS）生成，以及SSCs/祖细胞中的线粒体动力学紊乱和线粒体自噬。褪黑素对Cr（VI）诱导的线粒体自噬的保护作用是通过恢复METTL3介导的RNA mA修饰、激活线粒体融合蛋白MFN2和OPA1以及抑制线粒体自噬BNIP3/NIX受体途径来实现的。因此，我们的研究为负责线粒体动态平衡的基因调控网络中RNA mA修饰的分子机制提供了新的见解，也为治疗Cr（VI）诱导的男性生育力损伤奠定了新的实验基础。
