Leucine-Dependent SLC7A5-PGAM5 Interaction Promotes Advanced Atherosclerosis Through Hindering Mitochondrial Function...

The residual risks of advanced atherosclerosis remain substantial despite current preventive strategies and pharmacotherapy. Circulating branched-chain amino acids are biomarkers of cardiovascular disease risk. However, the mechanism of leucine in atherosclerosis progression remains unclear. Leucine transporter-SLC7A5-mediated leucine intake that promotes advanced atherosclerosis in mice, increasing apoptotic macrophages and lipids accumulation within plaques. Multi-omics analyses showed that leucine deprivation enhanced macrophage mitochondrial function and increased plaque CD5L^hi macrophages, under SLC7A5-deficiency-mediated leucine deprivation, these cells exhibited stronger oxidative phosphorylation and lipid metabolism. Mechanistically, leucine deficiency reduced SLC7A5-PGAM5 binding in macrophages, promoting PGAM5-NDUFV1 interaction and enhancing mitochondrial function, which attenuates atherosclerosis progression. Collectively, these findings elucidate the function and mechanism of SLC7A5 in Cd5l^hi macrophages, highlighting it as a potential therapeutic target. Strategies aimed at improving mitochondrial function also offer a promising approach for advanced atherosclerosis treatment.