Mitochondrial SLC3A1 regulates sexual dimorphism in cystinuria
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 <i>Slc3a1</i> knockout mice. We found that male mice lacking the <i>Slc3a1</i> gene exhibited more severe stone formation and renal injuries, unaffected by double knockout of another sex-dependent-expressed cystine transporter <i>Slc7a13</i> or orchidectomy procedure. Further investigations revealed aberrant mitochondrial functions as the primary factor contributing to the severity of cystinuria in <i>Slc3a1</i> knockout male mice. Mechanistically, higher SLC3A1 levels in male kidneys could enhance mitochondrial functions through modulation of mitochondrial NAD<sup>+</sup> uptake primarily in proximal tubule cells. Supplementation with an NAD<sup>+</sup> precursor rescued the sex differences caused by <i>Slc3a1</i> knockout. Our studies uncover the crucial role of <i>Slc3a1</i> in mitochondrial functions and provide novel insights into potential interventions for sexual dimorphism of cystinuria.
Authors
- Kaiyuan Wang
- Yi Zhong (ORCID: https://orcid.org/0009-0000-8183-838X)
- Yuting Guan (ORCID: https://orcid.org/0000-0003-1866-270X)
- Jiaxin Huang (ORCID: https://orcid.org/0000-0001-8095-3343)
- Kai‐Hsin Lin (ORCID: https://orcid.org/0000-0002-5833-7066)
- Xiangchen Gu (ORCID: https://orcid.org/0000-0003-1159-8565)
- Guofeng Xu (ORCID: https://orcid.org/0000-0002-5104-5386)
- Hongquan Geng (ORCID: https://orcid.org/0000-0003-4722-416X)
- Shengnan Liu (ORCID: https://orcid.org/0000-0003-3744-2972)
- Dali Li (ORCID: https://orcid.org/0000-0001-7214-4386)
- Fubin Zhong (ORCID: https://orcid.org/0000-0003-1496-9050)
- Jingyi Su
- Qihui Wu
- Yongdong Pan
Institutions
- Tongji University (CN)
- Chongqing Normal University (CN)
- XinHua Hospital (CN)
- Shanghai University of Traditional Chinese Medicine (CN)
- Yueyang Hospital (CN)
- Children's Hospital of Fudan University (CN)
- East China Normal University (CN)
Publication Details
- Journal
- Genes & Diseases
- Published
- 2024-11-29
- DOI
- https://doi.org/10.1016/j.gendis.2024.101472
- Citations
- 4
- Primary Topic
- Porphyrin Metabolism and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- National Natural Science Foundation of China
- Science and Technology Commission of Shanghai Municipality
- East China Normal University
- Natural Science Foundation of Chongqing
- Centre Scientifique et Technique du Bâtiment
- Shanghai Rising-Star Program