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

• Published in: Cell death & disease Vol. 15; no. 11; pp. 851 - 10
• Main Authors: Chiou, Shene, Cawthorne, Wayne, Soerianto, Thomas, Hofferek, Vinzenz, Patel, Komal M., Garnish, Sarah E., Tovey Crutchfield, Emma C., Hall, Cathrine, Hildebrand, Joanne M., McConville, Malcolm J., Lawlor, Kate E., Hawkins, Edwin D., Samson, Andre L., Murphy, James M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.11.2024; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/51; 14/63; 631/136/334/1874/345; 631/80/82/2344; 64/60; 82/16; 96/95; Age; Animals; Antibodies; Arteriosclerosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell death; Immunology; Life Sciences; Lysozyme; Macrophages; Macrophages - metabolism; Male; MAP kinase; Mice; Mice, Inbred C57BL; Necroptosis; Neurodegeneration; Protein Kinases - metabolism; Sperm; Spermatozoa - metabolism; Testes; Testis - metabolism; Testosterone; Testosterone - metabolism; Tubules
• ISSN: 2041-4889; 2041-4889
• 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.