Abstract
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.
Highlights
Necroptosis is a form of programmed necrotic cell death caused by the tumor necrosis factor family of cytokines (Christofferson and Yuan, 2010; Vandenabeele et al, 2010)
While conducting a study investigating the impact of necroptosis on the progression of atherosclerosis (Meng et al, 2015), we serendipitously found that the male reproductive organ of mice with Ripk3 and Mlkl gene knockout looked remarkably young even at advanced ages
Close examination revealed that the epithelium of the seminal vesicles from 18-month-old wild-type mice showed irregularities, with spaces separating the epithelium and the liquid compartment, whereas the seminal-vesicle epithelial cells from the age-matched Ripk3-knockout mice were tightly packed, just as they are in young mice (Figure 1—figure supplement 1C)
Summary
Necroptosis is a form of programmed necrotic cell death caused by the tumor necrosis factor family of cytokines (Christofferson and Yuan, 2010; Vandenabeele et al, 2010). Upon RIPK3 phosphorylation on serine and threonine of human MLKL or the mouse equivalent of serine 345, serine 347, and threonine 349, MLKL forms oligomers and translocates to the plasma membrane, where it disrupts membrane integrity, resulting in necrotic cell death (Cai et al, 2014; Chen et al, 2014; Hildebrand et al, 2014; Murphy et al, 2013; Rodriguez et al, 2016; Sun et al, 2012; Wang et al, 2014)
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