MLKL deficiency elevates testosterone production in male mice independently of necroptotic functions
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.
Authors
- Emma C. Tovey Crutchfield (ORCID: https://orcid.org/0000-0003-0379-2931)
- Joanne M. Hildebrand (ORCID: https://orcid.org/0000-0002-1456-2042)
- Shene Chiou (ORCID: https://orcid.org/0000-0003-1295-2183)
- Sarah E. Garnish (ORCID: https://orcid.org/0000-0002-9415-1517)
- James M. Murphy (ORCID: https://orcid.org/0000-0003-0195-3949)
- Wayne Cawthorne (ORCID: https://orcid.org/0009-0001-8467-8091)
- Malcolm J. McConville (ORCID: https://orcid.org/0000-0002-7107-7887)
- Edwin D. Hawkins (ORCID: https://orcid.org/0000-0002-3686-8261)
- Kate E. Lawlor (ORCID: https://orcid.org/0000-0003-0471-6842)
- Vinzenz Hofferek (ORCID: https://orcid.org/0000-0002-6150-1453)
- Cathrine Hall (ORCID: https://orcid.org/0009-0005-1004-9435)
- André L. Samson (ORCID: https://orcid.org/0000-0002-0637-2716)
- Komal Patel (ORCID: https://orcid.org/0000-0003-2976-7638)
- Thomas Soerianto (ORCID: https://orcid.org/0009-0005-0452-7074)
Institutions
- The Royal Melbourne Hospital (AU)
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Discovery Institute (US)
- Hudson Institute of Medical Research (AU)
- Monash University (AU)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2024-11-21
- DOI
- https://doi.org/10.1038/s41419-024-07242-z
- Citations
- 2
- Primary Topic
- Cell death mechanisms and regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.47
Funders
- Australian Government
- Medical Research Council
- National Health and Medical Research Council