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 reproduc...
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Nature Publishing Group
2024-11-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07242-z |
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| author | Shene Chiou Wayne Cawthorne Thomas Soerianto Vinzenz Hofferek Komal M. Patel Sarah E. Garnish Emma C. Tovey Crutchfield Cathrine Hall Joanne M. Hildebrand Malcolm J. McConville Kate E. Lawlor Edwin D. Hawkins Andre L. Samson James M. Murphy |
| author_facet | Shene Chiou Wayne Cawthorne Thomas Soerianto Vinzenz Hofferek Komal M. Patel Sarah E. Garnish Emma C. Tovey Crutchfield Cathrine Hall Joanne M. Hildebrand Malcolm J. McConville Kate E. Lawlor Edwin D. Hawkins Andre L. Samson James M. Murphy |
| author_sort | Shene Chiou |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-3e983790f4d740f6875bec76ced943af |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-3e983790f4d740f6875bec76ced943af2025-08-20T02:22:16ZengNature Publishing GroupCell Death and Disease2041-48892024-11-01151111010.1038/s41419-024-07242-zMLKL deficiency elevates testosterone production in male mice independently of necroptotic functionsShene Chiou0Wayne Cawthorne1Thomas Soerianto2Vinzenz Hofferek3Komal M. Patel4Sarah E. Garnish5Emma C. Tovey Crutchfield6Cathrine Hall7Joanne M. Hildebrand8Malcolm J. McConville9Kate E. Lawlor10Edwin D. Hawkins11Andre L. Samson12James M. Murphy13Walter and Eliza Hall Institute of Medical ResearchWalter and Eliza Hall Institute of Medical ResearchDepartment of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology InstituteDepartment of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology InstituteWalter and Eliza Hall Institute of Medical ResearchWalter and Eliza Hall Institute of Medical ResearchWalter and Eliza Hall Institute of Medical ResearchWalter and Eliza Hall Institute of Medical ResearchWalter and Eliza Hall Institute of Medical ResearchDepartment of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology InstituteCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical ResearchWalter and Eliza Hall Institute of Medical ResearchWalter and Eliza Hall Institute of Medical ResearchWalter and Eliza Hall Institute of Medical ResearchAbstract 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.https://doi.org/10.1038/s41419-024-07242-z |
| spellingShingle | Shene Chiou Wayne Cawthorne Thomas Soerianto Vinzenz Hofferek Komal M. Patel Sarah E. Garnish Emma C. Tovey Crutchfield Cathrine Hall Joanne M. Hildebrand Malcolm J. McConville Kate E. Lawlor Edwin D. Hawkins Andre L. Samson James M. Murphy MLKL deficiency elevates testosterone production in male mice independently of necroptotic functions Cell Death and Disease |
| title | MLKL deficiency elevates testosterone production in male mice independently of necroptotic functions |
| title_full | MLKL deficiency elevates testosterone production in male mice independently of necroptotic functions |
| title_fullStr | MLKL deficiency elevates testosterone production in male mice independently of necroptotic functions |
| title_full_unstemmed | MLKL deficiency elevates testosterone production in male mice independently of necroptotic functions |
| title_short | MLKL deficiency elevates testosterone production in male mice independently of necroptotic functions |
| title_sort | mlkl deficiency elevates testosterone production in male mice independently of necroptotic functions |
| url | https://doi.org/10.1038/s41419-024-07242-z |
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