MLKL deficiency elevates testosterone production in male mice independently of necroptotic functions

Chiou, S; Cawthorne, W; Soerianto, T; Hofferek, V; Patel, KM; Garnish, SE; Tovey Crutchfield, EC; Hall, C; Hildebrand, JM; McConville, MJ; Lawlor, KE; Hawkins, ED; Samson, AL; Murphy, JM

Author(s): Chiou, S; Cawthorne, W; Soerianto, T; Hofferek, V; Patel, KM; Garnish, SE; Tovey Crutchfield, EC; Hall, C; Hildebrand, JM; McConville, MJ; Lawlor, KE; Hawkins, ED; Samson, AL; Murphy, JM;
Details: Publication Year 2024-11-21,Volume 15,Issue #11,Page 851
Journal Title: Cell Death & Disease
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.
Publisher: Springer Nature
Keywords: Animals; Male; *Testosterone/metabolism; Mice; *Necroptosis; *Protein Kinases/metabolism; *Testis/metabolism; Mice, Inbred C57BL; Macrophages/metabolism; Spermatozoa/metabolism
Research Division(s): Inflammation; Immunology
PubMed ID: 39572538
Publisher's Version: https://doi.org/10.1038/s41419-024-07242-z
Open Access at Publisher's Site: https://doi.org/10.1038/s41419-024-07242-z
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-01-21 10:07:44

Last Modified: 2025-01-21 11:03:01