Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
Cell Death Dis. 2024 Nov 21;15(11):851. doi: 10.1038/s41419-024-07242-z.
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.
混合谱系激酶结构域样（MLKL）是一种假激酶，其作为坏死性细胞死亡途径的最终效应因子而广为人知。MLKL 介导的坏死性细胞死亡长期以来与各种与年龄相关的病理学有关，包括神经退行性变、动脉粥样硬化和男性生殖能力下降，但其中许多归因仍存在争议。在这里，我们研究了 MLKL 和坏死性细胞死亡在成年小鼠睾丸中的作用：睾丸由产生精子的生精小管和周围产生睾丸激素的间质组成。我们发现，生精小管内的精子产生细胞缺乏关键的坏死性细胞死亡介质的表达，因此对促坏死性细胞死亡的刺激具有抗性。相比之下，坏死性细胞死亡途径在睾丸间质中协调表达，使该隔室中的细胞，特别是溶酶体阳性巨噬细胞，容易发生坏死性细胞死亡。我们还揭示了 MLKL 在调节睾丸激素水平方面的非坏死性细胞死亡作用。因此，MLKL 在小鼠睾丸中发挥两种作用 - 一种涉及巨噬细胞对坏死性细胞损伤的典型反应，另一种是在男性生殖激素控制中的非典型功能。
