Su Jingyi, Pan Yongdong, Zhong Fengbo, Zhong Yi, Huang Jiaxin, Liu Shengnan, Wang Kaiyuan, Lin Kai, Gu Xiangchen, Li Dali, Wu Qihui, Geng Hongquan, Guan Yuting, Xu Guofeng
Department of Pediatric Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Genes Dis. 2024 Nov 29;12(3):101472. doi: 10.1016/j.gendis.2024.101472. eCollection 2025 May.
Cystinuria is the most common inheritable cause of kidney stone disease, with males exhibiting a higher susceptibility than females. However, the cellular origin and underlying mechanisms of sex differences in cystinuria remain elusive. This study aims to investigate the mechanism using knockout mice. We found that male mice lacking the gene exhibited more severe stone formation and renal injuries, unaffected by double knockout of another sex-dependent-expressed cystine transporter or orchidectomy procedure. Further investigations revealed aberrant mitochondrial functions as the primary factor contributing to the severity of cystinuria in knockout male mice. Mechanistically, higher SLC3A1 levels in male kidneys could enhance mitochondrial functions through modulation of mitochondrial NAD uptake primarily in proximal tubule cells. Supplementation with an NAD precursor rescued the sex differences caused by knockout. Our studies uncover the crucial role of in mitochondrial functions and provide novel insights into potential interventions for sexual dimorphism of cystinuria.
胱氨酸尿症是肾结石疾病最常见的可遗传病因，男性比女性表现出更高的易感性。然而，胱氨酸尿症性别差异的细胞起源和潜在机制仍不清楚。本研究旨在使用基因敲除小鼠来研究其机制。我们发现，缺乏该基因的雄性小鼠表现出更严重的结石形成和肾损伤，不受另一种性别依赖性表达的胱氨酸转运蛋白双敲除或睾丸切除术的影响。进一步的研究揭示，线粒体功能异常是导致基因敲除雄性小鼠胱氨酸尿症严重程度的主要因素。从机制上讲，雄性肾脏中较高的SLC3A1水平可通过主要调节近端小管细胞中线粒体NAD的摄取来增强线粒体功能。补充NAD前体可挽救基因敲除引起的性别差异。我们的研究揭示了该基因在线粒体功能中的关键作用，并为胱氨酸尿症性别二态性的潜在干预提供了新的见解。
