Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, USA.
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
J Biol Chem. 2022 Jul;298(7):102077. doi: 10.1016/j.jbc.2022.102077. Epub 2022 May 25.
During epididymal transit, redox remodeling protects mammalian spermatozoa, preparing them for survival in the subsequent journey to fertilization. However, molecular mechanisms of redox regulation in sperm development and maturation remain largely elusive. In this study, we report that thioredoxin-glutathione reductase (TXNRD3), a thioredoxin reductase family member particularly abundant in elongating spermatids at the site of mitochondrial sheath formation, regulates redox homeostasis to support male fertility. Using Txnrd3 mice, our biochemical, ultrastructural, and live cell imaging analyses revealed impairments in sperm morphology and motility under conditions of TXNRD3 deficiency. We find that mitochondria develop more defined cristae during capacitation in wildtype sperm. Furthermore, we show that absence of TXNRD3 alters thiol redox status in both the head and tail during sperm maturation and capacitation, resulting in defective mitochondrial ultrastructure and activity under capacitating conditions. These findings provide insights into molecular mechanisms of redox homeostasis and bioenergetics during sperm maturation, capacitation, and fertilization.
在附睾转运过程中，氧化还原重塑保护哺乳动物精子，使它们为随后的受精之旅做好生存准备。然而，精子发生和成熟过程中氧化还原调节的分子机制在很大程度上仍未被揭示。在这项研究中，我们报告称，硫氧还蛋白-谷胱甘肽还原酶（TXNRD3）是一种硫氧还蛋白还原酶家族成员，在形成线粒体鞘的伸长精子中特别丰富，它调节氧化还原平衡以支持男性生育能力。使用 Txnrd3 小鼠，我们的生化、超微结构和活细胞成像分析表明，在 TXNRD3 缺乏的情况下，精子形态和运动能力受损。我们发现，在野生型精子中，线粒体在获能过程中形成更明确的嵴。此外，我们表明，TXNRD3 的缺失会改变精子成熟和获能过程中头部和尾部的硫醇氧化还原状态，导致在获能条件下线粒体超微结构和活性受损。这些发现为精子成熟、获能和受精过程中的氧化还原平衡和生物能量学的分子机制提供了新的见解。
