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 decl...

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Published inCell 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
LanguageEnglish
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
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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.
AbstractList 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.
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.
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.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.
ArticleNumber 851
Author Hall, Cathrine
McConville, Malcolm J.
Chiou, Shene
Patel, Komal M.
Hawkins, Edwin D.
Garnish, Sarah E.
Soerianto, Thomas
Hildebrand, Joanne M.
Murphy, James M.
Tovey Crutchfield, Emma C.
Lawlor, Kate E.
Hofferek, Vinzenz
Samson, Andre L.
Cawthorne, Wayne
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Snippet Mixed lineage kinase domain-like (MLKL) is a pseudokinase, best known for its role as the terminal effector of the necroptotic cell death pathway....
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....
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SubjectTerms 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
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Title MLKL deficiency elevates testosterone production in male mice independently of necroptotic functions
URI https://link.springer.com/article/10.1038/s41419-024-07242-z
https://www.ncbi.nlm.nih.gov/pubmed/39572538
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Volume 15
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