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Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
Published on: August 7, 2018
RIPK1-RIPK3-MLKL-dependent necrosis promotes the aging of mouse male reproductive system
Dianrong Li1, Lingjun Meng1, Tao Xu1
1National Institute of Biological Sciences, Beijing, China.
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.
Insights
Necroptosis, a cell death pathway involving RIPK1/RIPK3 and MLKL, drives aging in male mouse reproductive systems. Inhibiting this pathway preserves youthful function and morphology in aging mice.
Area of Science:
- Cellular Biology
- Reproductive Biology
- Aging Research
Background:
- Necroptosis is a programmed cell death pathway mediated by RIPK1, RIPK3, and MLKL.
- Age-related deterioration affects male reproductive organs, impacting function and morphology.
Purpose of the Study:
- To investigate the role of necroptosis in the aging of male reproductive organs.
- To determine if inhibiting necroptosis can prevent or reverse age-related decline in male reproductive function.
Main Methods:
- Utilized knockout mice lacking Ripk3 or Mlkl to assess reproductive organ aging.
- Examined necroptosis markers (RIPK3 phosphorylation of MLKL) in testes of young and old wild-type mice.
- Administered a necroptotic stimulus to young wild-type mouse testes to observe aging effects.
- Treated wild-type mice with an RIPK1 inhibitor to evaluate its impact on reproductive aging.
Main Results:
- Male reproductive organs in Ripk3- and Mlkl-knockout mice maintained youthful characteristics into advanced age.
- RIPK3-MLKL phosphorylation, a necroptosis marker, was present in testes of old but not young wild-type mice.
- A necroptotic stimulus accelerated aging in young wild-type mouse testes.
- RIPK1 inhibition prevented age-related changes in reproductive organs of wild-type mice.
Conclusions:
- Necroptosis in the testes significantly contributes to the aging-associated deterioration of the male reproductive system.
- Targeting necroptosis pathways, specifically RIPK1, offers a potential therapeutic strategy to mitigate male reproductive aging.
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