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Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
Published on: August 7, 2018
MLKL deficiency elevates testosterone production in male mice independently of necroptotic functions
Shene Chiou1,2, Wayne Cawthorne1,2, Thomas Soerianto3
1Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
Abstract:
Mixed lineage kinase domain-like (MLKL) is a pseudokinase, best known for its role as the terminal effector of the necroptotic cell death pathway. MLKL-mediated necroptosis has long been linked to various age-related pathologies including neurodegeneration, atherosclerosis and male reproductive decline, however many of these attributions remain controversial. Here, we investigated the role of MLKL and necroptosis in the adult mouse testis: an organ divided into sperm-producing seminiferous tubules and the surrounding testosterone-producing interstitium. We find that sperm-producing cells within seminiferous tubules lack expression of key necroptotic mediators and thus are resistant to a pro-necroptotic challenge. By comparison, coordinated expression of the necroptotic pathway occurs in the testicular interstitium, rendering cells within this compartment, especially the lysozyme-positive macrophages, vulnerable to necroptotic cell death. We also uncover a non-necroptotic role for MLKL in regulating testosterone levels. Thus, MLKL serves two roles in the mouse testes - one involving the canonical response of macrophages to necroptotic insult, and the other a non-canonical function in male reproductive hormone control.
Insights
Mixed lineage kinase domain-like (MLKL) protein has dual roles in the adult mouse testes. It mediates necroptosis in interstitial macrophages and non-canonically regulates testosterone levels.
Area of Science:
- Cell Biology
- Reproductive Biology
- Immunology
Background:
- Mixed lineage kinase domain-like (MLKL) is a pseudokinase and the terminal effector of necroptosis.
- MLKL-mediated necroptosis is implicated in age-related diseases, but its role in the adult mouse testis is unclear.
- The testis comprises seminiferous tubules (sperm production) and interstitium (testosterone production).
Purpose of the Study:
- To investigate the role of MLKL and necroptosis in the adult mouse testis.
- To determine the cell-type specificity of necroptosis pathway activation in the testis.
- To explore potential non-necroptotic functions of MLKL in male reproduction.
Main Methods:
- Analysis of MLKL and necroptosis pathway component expression in different testicular compartments.
- Assessment of testicular cell susceptibility to necroptotic stimuli.
- Evaluation of MLKL's impact on testosterone levels in vivo.
Main Results:
- Sperm-producing cells in seminiferous tubules lack key necroptotic mediators and are resistant to necroptosis.
- The necroptotic pathway is active in the testicular interstitium, particularly in lysozyme-positive macrophages, making them susceptible to necroptosis.
- MLKL was found to have a non-necroptotic role in regulating testosterone levels.
Conclusions:
- MLKL has a dual role in the adult mouse testis: mediating necroptosis in interstitial macrophages and regulating testosterone levels through a non-canonical pathway.
- These findings highlight the complex functions of MLKL beyond its established role in necroptosis and its significance in male reproductive health.
