Abstract

Hyperuricemia is a common metabolic disease and an important risk factor for low testosterone levels in men. The functional homeostasis of stem Leydig cells (SLCs) is crucial for maintaining testosterone levels. However, the potential molecular mechanism of how high uric acid (UA) levels affect SLC function remains to be elucidated. Here, we reveal that at the single-cell RNA sequencing level, SLCs exhibit senescence under high UA conditions. Mechanistically, UA binds to CCDC90B, leading to its significant accumulation within cells. This exacerbates the influx of calcium ions into mitochondria, resulting in mitochondrial quality control (MQC) imbalance. In addition, at the level of organoids and transgenic mice, we observe SLC senescence is alleviated and considerable testosterone recovery after AAV8-CCDC90B treatment. In summary, these results indicate that SLC senescence under high UA is regulated in a MQC-dependent manner, with CCDC90B being a key regulatory target. Meanwhile, AAV-mediated gene therapy may offer a promising therapeutic approach for patients with low testosterone levels.