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⁺ uptake primarily in proximal tubule cells. Supplementation with an NAD⁺ 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.