Gong Yabin, Zhang Zhilong, Chang Zhanglin, Zhou Hao, Zhao Ruqian, He Bin
Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China.
MOE Joint International Research Laboratory of Animal Health and Food Safety, Nanjing Agricultural University, Nanjing 210095, PR China.
Aging (Albany NY). 2018 Nov 6;10(11):3104-3116. doi: 10.18632/aging.101614.
The rapid and efficient clearance of apoptotic germ cells (GCs) by Sertoli cells (SCs) is important for spermatogenesis. High mitochondrial activity in phagocytes is critical for continued clearance of apoptotic cells. However, the underlying molecular mechanism is poorly understood. Glycogen synthase kinase-3α (GSK3α) is a protein kinase that participates in the regulation of mitochondrial activity. Immunohistochemistry evidenced the predominant presence of the Ser21 phosphorylation GSK3α (inactivation) signal in SCs. Heat shock-induced apoptosis of GCs and dephosphorylation of GSK3α in SCs is a perfect model to investigate the role of GSK3α in phagocytic action. The number of apoptotic GCs was significantly lower in GSK3α inhibitor pre-treated mice with HS compared to normal control. phagocytosis assays shown that the phagocytic activity in GSK3α activated SCs was downregulated, while GSK3α inhibitor supplementation restored this process. Moreover, GSK3α activation participates in the alteration of the mitochondrial ultrastructure and activity. In particular, GSK3α activation inhibits mitochondrial fission via phosphorylation of dynamin related protein 1 at Ser637. Changes of mitochondrial activity resulted in the accumulation of lipid droplets and the alteration of metabolism pattern in SCs. In summary, our results demonstrate that inactivation of GSK3α is required for mitochondria-mediated apoptotic GCs phagocytosis in SCs.
支持细胞（SCs）对凋亡生殖细胞（GCs）的快速有效清除对精子发生很重要。吞噬细胞中的高线粒体活性对于持续清除凋亡细胞至关重要。然而，其潜在的分子机制尚不清楚。糖原合酶激酶-3α（GSK3α）是一种参与线粒体活性调节的蛋白激酶。免疫组织化学证明支持细胞中主要存在Ser21磷酸化的GSK3α（失活）信号。热休克诱导的生殖细胞凋亡和支持细胞中GSK3α的去磷酸化是研究GSK3α在吞噬作用中作用的完美模型。与正常对照相比，用GSK3α抑制剂预处理的热休克小鼠中凋亡生殖细胞的数量明显减少。吞噬试验表明，GSK3α激活的支持细胞中的吞噬活性下调，而补充GSK3α抑制剂可恢复此过程。此外，GSK3α激活参与线粒体超微结构和活性的改变。特别是，GSK3α激活通过在Ser637处磷酸化动力相关蛋白1来抑制线粒体分裂。线粒体活性的变化导致支持细胞中脂滴的积累和代谢模式的改变。总之，我们的结果表明，GSK3α失活是支持细胞中线粒体介导的凋亡生殖细胞吞噬所必需的。
