MLKL deficiency elevates testosterone production in male mice independently of necroptotic functions
- PMID: 39572538
- PMCID: PMC11582601
- DOI: 10.1038/s41419-024-07242-z
MLKL deficiency elevates testosterone production in male mice independently of necroptotic functions
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.
© 2024. The Author(s).
Conflict of interest statement
Competing interests: KMP, JMH, KEL, ALS, and JMM contribute to or have contributed to a project developing necroptosis inhibitors in collaboration with Anaxis Pharma. The other authors declare no competing interests. Ethics declaration: All experiments were approved by the WEHI Animal Ethics Committee following the Prevention of Cruelty to Animals Act (1996) and the Australian National Health and Medical Research Council Code of Practice for the Care and Use of Animals for Scientific Purposes (1997).
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