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

Area of Science:

• Reproductive Biology
• Cell Biology
• Aging Research

Background:

• Age-related testicular dysfunction, including late-onset hypogonadism (LOH), impacts male health.
• The precise mechanisms driving LOH and testicular aging are not fully understood.

Purpose of the Study:

• To investigate the role of Sertoli cells (SCs) in age-related testicular dysfunction.
• To identify molecular mechanisms underlying LOH and explore therapeutic targets.

Main Methods:

• Single-cell RNA sequencing of human testes from LOH patients.
• Lysosomal acidity probing and metabolic analysis of SCs.
• High-fat diet-induced LOH model in mice and therapeutic intervention with TRPML1 agonist.

Main Results:

• Aged SCs exhibit compromised lysosomal function, impaired autophagy, and phagocytosis, termed phago-/auto-lysosomal deregulated SCs.
• These SCs accumulate metabolites like cholesterol and show increased inflammatory gene expression.
• High-fat diet induced similar SC dysfunction in mice, recapitulating LOH features.
• TRPML1 agonist administration restored lysosomal function and normalized testosterone levels in mice.

Conclusions:

• Sertoli cells are critical regulators of testicular aging and metabolic homeostasis.
• Dysfunctional lysosomes in SCs contribute significantly to LOH.
• Targeting lysosomal function, specifically via TRPML1, presents a promising therapeutic strategy for LOH.