RIPK1-RIPK3-MLKL-dependent Necrosis Promotes the Aging of Mouse Male Reproductive System

Overview

Journal Elife

Specialty Biology

Date 2017 Aug 16

PMID 28807105

Citations 45

Authors

Dianrong Li

Lingjun Meng

Tao Xu

Yaning Su

Xiao Liu

Zhiyuan Zhang

Xiaodong Wang

Affiliations

Soon will be listed here.

Abstract

A pair of kinases, RIPK1 and RIPK3, as well as the RIPK3 substrate MLKL cause a form of programmed necrotic cell death in mammals termed necroptosis. We report here that male reproductive organs of both 3- and -knockout mice retain 'youthful' morphology and function into advanced age, while those of age-matched wild-type mice deteriorate. The RIPK3 phosphorylation of MLKL, the activation marker of necroptosis, is detected in spermatogonial stem cells in the testes of old but not in young wild-type mice. When the testes of young wild-type mice are given a local necroptotic stimulus, their reproductive organs showed accelerated aging. Feeding of wild-type mice with an RIPK1 inhibitor prior to the normal onset of age-related changes in their reproductive organs blocked the appearance of signs of aging. Thus, necroptosis in testes promotes the aging-associated deterioration of the male reproductive system in mice.

Citing Articles

Safety, Pharmacokinetics and Target Engagement of a Novel Brain Penetrant RIPK1 Inhibitor (SIR9900) in Healthy Adults and Elderly Participants.

Gonen O, Porter T, Wang B, Xue F, Ma Y, Song L Clin Transl Sci. 2025; 18(2):e70151.

PMID: 39960838 PMC: 11832029. DOI: 10.1111/cts.70151.

RIP kinases and necroptosis in aging and aging-related diseases.

Yang Y, Li X, Zhang T, Xu D Life Med. 2025; 1(1):2-20.

PMID: 39872161 PMC: 11749793. DOI: 10.1093/lifemedi/lnac003.

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

Chiou S, Cawthorne W, Soerianto T, Hofferek V, Patel K, Garnish S Cell Death Dis. 2024; 15(11):851.

PMID: 39572538 PMC: 11582601. DOI: 10.1038/s41419-024-07242-z.

TBK1-associated adapters TANK and AZI2 protect mice against TNF-induced cell death and severe autoinflammatory diseases.

Ujevic A, Knizkova D, Synackova A, Pribikova M, Trivic T, Dalinskaya A Nat Commun. 2024; 15(1):10013.

PMID: 39562788 PMC: 11576971. DOI: 10.1038/s41467-024-54399-4.

A phase I randomized study to evaluate safety, pharmacokinetics, and pharmacodynamics of SIR2446M, a selective RIPK1 inhibitor, in healthy participants.

Sun A, Gillies J, Shen Y, Deng H, Xue F, Ma Y Clin Transl Sci. 2024; 17(7):e13857.

PMID: 38949195 PMC: 11215690. DOI: 10.1111/cts.13857.

References

Hooley R, Paterson M, Brown P, Kerr K, Saunders P . Intra-testicular injection of adenoviral constructs results in Sertoli cell-specific gene expression and disruption of the seminiferous epithelium. Reproduction. 2008; 137(2):361-70. PMC: 2709205. DOI: 10.1530/REP-08-0247. View

Cho Y, Challa S, Moquin D, Genga R, Ray T, Guildford M . Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009; 137(6):1112-23. PMC: 2727676. DOI: 10.1016/j.cell.2009.05.037. View

Newton K, Sun X, Dixit V . Kinase RIP3 is dispensable for normal NF-kappa Bs, signaling by the B-cell and T-cell receptors, tumor necrosis factor receptor 1, and Toll-like receptors 2 and 4. Mol Cell Biol. 2004; 24(4):1464-9. PMC: 344190. DOI: 10.1128/MCB.24.4.1464-1469.2004. View

Vermeulen A, Kaufman J, Giagulli V . Influence of some biological indexes on sex hormone-binding globulin and androgen levels in aging or obese males. J Clin Endocrinol Metab. 1996; 81(5):1821-6. DOI: 10.1210/jcem.81.5.8626841. View

Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G . Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol. 2010; 11(10):700-14. DOI: 10.1038/nrm2970. View

Johnson S, Dunleavy J, Gemmell N, Nakagawa S . Consistent age-dependent declines in human semen quality: a systematic review and meta-analysis. Ageing Res Rev. 2014; 19:22-33. DOI: 10.1016/j.arr.2014.10.007. View

Murphy J, Czabotar P, Hildebrand J, Lucet I, Zhang J, Alvarez-Diaz S . The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity. 2013; 39(3):443-53. DOI: 10.1016/j.immuni.2013.06.018. View

van Bragt M, Roepers-Gajadien H, Korver C, Bogerd J, Okuda A, Eggen B . Expression of the pluripotency marker UTF1 is restricted to a subpopulation of early A spermatogonia in rat testis. Reproduction. 2008; 136(1):33-40. DOI: 10.1530/REP-07-0536. View

Chen X, Li W, Ren J, Huang D, He W, Song Y . Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death. Cell Res. 2013; 24(1):105-21. PMC: 3879712. DOI: 10.1038/cr.2013.171. View

10.

Sun L, Wang H, Wang Z, He S, Chen S, Liao D . Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012; 148(1-2):213-27. DOI: 10.1016/j.cell.2011.11.031. View

11.

Chang Y, Lee-Chang J, Panneerdoss S, MacLean 2nd J, Rao M . Isolation of Sertoli, Leydig, and spermatogenic cells from the mouse testis. Biotechniques. 2011; 51(5):341-2, 344. PMC: 3774005. DOI: 10.2144/000113764. View

12.

Ren Y, Su Y, Sun L, He S, Meng L, Liao D . Discovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome. J Med Chem. 2016; 60(3):972-986. DOI: 10.1021/acs.jmedchem.6b01196. View

13.

Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S . Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol. 2001; 1(6):489-95. DOI: 10.1038/82732. View

14.

Chigurupati S, Son T, Hyun D, Lathia J, Mughal M, Savell J . Lifelong running reduces oxidative stress and degenerative changes in the testes of mice. J Endocrinol. 2008; 199(2):333-41. PMC: 2597502. DOI: 10.1677/JOE-08-0306. View

15.

Robinson N, McComb S, Mulligan R, Dudani R, Krishnan L, Sad S . Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium. Nat Immunol. 2012; 13(10):954-62. PMC: 4005791. DOI: 10.1038/ni.2397. View

16.

Finch C, GIRGIS F . Enlarged seminal vesicles of senescent C57BL-6J mice. J Gerontol. 1974; 29(2):134-8. DOI: 10.1093/geronj/29.2.134. View

17.

Cai Z, Jitkaew S, Zhao J, Chiang H, Choksi S, Liu J . Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat Cell Biol. 2013; 16(1):55-65. PMC: 8369836. DOI: 10.1038/ncb2883. View

18.

Rodriguez D, Weinlich R, Brown S, Guy C, Fitzgerald P, Dillon C . Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis. Cell Death Differ. 2015; 23(1):76-88. PMC: 4815980. DOI: 10.1038/cdd.2015.70. View

19.

Pettan-Brewer C, Treuting P . Practical pathology of aging mice. Pathobiol Aging Age Relat Dis. 2012; 1. PMC: 3417704. DOI: 10.3402/pba.v1i0.7202. View

20.

Tsai M, Yeh S, Wang R, Yeh S, Zhang C, Lin H . Differential effects of spermatogenesis and fertility in mice lacking androgen receptor in individual testis cells. Proc Natl Acad Sci U S A. 2006; 103(50):18975-80. PMC: 1748162. DOI: 10.1073/pnas.0608565103. View