RIPK1-RIPK3-MLKL-dependent necrosis promotes the aging of mouse male reproductive system
RIPK1-RIPK3-MLKL-dependent necrosis promotes the aging of mouse male reproductive system
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DOI：
10.7554/elife.27692.001
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发表时间：
2017-08-15
期刊：
影响因子：
7.7
通讯作者：
Wang, Xiaodong
中科院分区：
文献类型：
--
作者：
Li, Dianrong;Meng, Lingjun;Wang, Xiaodong
一对激酶RIPK1和RIPK3以及RIPK3底物MLKL在哺乳动物中引起一种称为坏死性凋亡的程序性坏死细胞死亡。我们在这里报告说，Ripk3和Mlkl基因敲除小鼠的雄性生殖器官保持年轻的形态和功能，进入老年，而年龄匹配的野生型小鼠退化。MLKL的RIPK3磷酸化是坏死性凋亡的激活标志物，在老年野生型小鼠睾丸的精原干细胞中检测到，但在年轻野生型小鼠中未检测到。当年轻的野生型小鼠的睾丸被给予局部坏死性刺激时，它们的生殖器官显示出加速老化。在野生型小鼠的生殖器官中与年龄相关的变化正常发生之前，用RIPK1抑制剂喂养野生型小鼠，阻止了衰老迹象的出现。因此，睾丸坏死性凋亡促进了小鼠雄性生殖系统的衰老相关恶化。
A pair of kinases, RIPK1 and RIPK3, as well as the RIPK3 substrate MLKL cause a form of programmed necrotic cell death in mammals termed necroptosis. We report here that male reproductive organs of both Ripk3- and Mlkl-knockout mice retain youthful morphology and function into advanced age, while those of age-matched wild-type mice deteriorate. The RIPK3 phosphorylation of MLKL, the activation marker of necroptosis, is detected in spermatogonial stem cells in the testes of old but not in young wild-type mice. When the testes of young wild-type mice are given a local necroptotic stimulus, their reproductive organs showed accelerated aging. Feeding of wild-type mice with an RIPK1 inhibitor prior to the normal onset of age-related changes in their reproductive organs blocked the appearance of signs of aging. Thus, necroptosis in testes promotes the aging-associated deterioration of the male reproductive system in mice.