Mitochondrial SLC3A1 regulates sexual dimorphism in cystinuria  

作　　者：Jingyi Su Yongdong Pan Fengbo Zhong Yi Zhong Jiaxin Huang Shengnan Liu Kaiyuan Wang Kai Lin Xiangchen Gu Dali Li Qihui Wu Hongquan Geng Yuting Guan Guofeng Xu 

机构地区：[1]Department of Pediatric Urology,Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200092,China [2]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 [3]Department of Nephrology,Yueyang Hospital of Integrated Traditional Chinese and Western Medicine,Shanghai University of Traditional Chinese Medicine,Shanghai 200437,China [4]Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation,Clinical Research Center for Anesthesiology and Perioperative Medicine,Translational Research Institute of Brain and Brain-Like Intelligence,Shanghai Fourth People’s Hospital,School of Medicine,Tongji University,Shanghai 200434,China [5]Department of Urology,Children’s Hospital of Fudan University,Shanghai 201102,China [6]Chongqing Key Laboratory of Precision Optics,Chongqing Institute of East China Normal University,Chongqing 401120,China

出　　处：《Genes & Diseases》2025年第3期533-549,共17页基因与疾病(英文)

基　　金：supported by grants from the Science and Technology Commission of Shanghai Municipality of China(No.23Y21900102 to G.X.;23ZR1467900 to Q.W.);Shanghai Rising-Star Program(No.22QA1405900 to Y.G.);the National Key R&D Program of China(No.2022YFC2505400,2022YFC3400203 to Y.G.);the National Natural Science Foundation of China(No.82100773 to Y.G.;82101486,82371426 to Q.W.);the Natural Science Foundation of Chongqing,China(No.CSTB2022NSCQ-MSX1621 to Y.G.);the Ningxia Hui Autonomous Region Key Research and Development Project(China)(No.2022BFH02012 to Q.W.).

摘　　要：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 Slc3a1 knockout mice.We found that male mice lacking the Slc3a1 gene exhibited more severe stone formation and renal injuries,unaffected by double knockout of another sex-dependent-expressed cystine transporter Slc7a13 or orchidectomy procedure.Further investigations revealed aberrant mitochondrial functions as the primary factor contributing to the severity of cystinuria in Slc3a1 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 Slc3a1 knockout.Our studies uncover the crucial role of Slc3a1 in mitochondrial functions and provide novel insights into potential interventions for sexual dimorphism of cystinuria.

关 键 词：CYSTINURIA Kidney injury MITOCHONDRIA Sex bias Slc3a1 

分 类 号：R692[医药卫生—泌尿科学]