Targeting dysregulated phago-/auto-lysosomes in Sertoli cells to ameliorate late-onset hypogonadism

  • Nat Aging. 2024 Apr 22. doi: 10.1038/s43587-024-00614-2.
Zhiwen Deng  #  1  2 ,  Liangyu Zhao  #  1  3  4 ,  Sha Li  #  1  2 ,  Xiaoyang Chen  1  2 ,  Xiaohan Ling  1  2 ,  Jiajun Zheng  1  2 ,  Kunkun Yu  1  2 ,  Jing Xu  1 ,  Chencheng Yao  3 ,  Sha Han  3 ,  Jiayi Liang  1 ,  Huimin Feng  1 ,  Lanlan Wu  1 ,  Peng Li  3 ,  Ruhui Tian  3 ,  Tao Jing  3  5 ,  Yuxin Tang  4 ,  Yingbo Dai  4 ,  Minbo Yan  4 ,  Chenchen Wang  6 ,  Zheng Li  7 ,  Zhi Zhou  8  9
Affiliations
  • 1. School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 2. Shanghai Clinical Research and Trial Center, Shanghai, China.
  • 3. Department of Andrology, the Center for Men's Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4. Department of Urology, Department of Interventional Medicine, Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
  • 5. Department of Andrology, the Affiliated Hospital of Qingdao University, Qingdao, China.
  • 6. Shanghai Advanced Research Institute, Stem Cell and Reproductive Biology Laboratory, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 7. Department of Andrology, the Center for Men's Health, Urologic Medical Center, Shanghai Key Laboratory of Reproductive Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 8. School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
  • 9. Shanghai Clinical Research and Trial Center, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 38649614 DOI: 10.1038/s43587-024-00614-2
Abstract

Age-related changes in testicular function can impact health and well-being. The mechanisms underlying age-related testicular dysfunction, such as late-onset hypogonadism (LOH), remain incompletely understood. Using single-cell RNA Sequencing on human testes with LOH, we delineated Sertoli cells (SCs) as pivotal metabolic coordinators within the testicular microenvironment. In particular, lysosomal acidity probing revealed compromised degradative capacity in aged SCs, hindering Autophagy and phagocytic flux. Consequently, SCs accumulated metabolites, including Cholesterol, and have increased inflammatory gene expression; thus, we termed these cells as phago-/auto-lysosomal deregulated SCs. Exposure to a high-fat diet-induced phago-/auto-lysosomal dysregulated-like SCs, recapitulating LOH features in mice. Notably, efferent ductular injection and systemic TRPML1 agonist administration restored lysosomal function, normalizing testosterone deficiency and associated abnormalities in high-fat diet-induced LOH mice. Our findings underscore the central role of SCs in testis aging, presenting a promising therapeutic avenue for LOH.

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