Leucine-Dependent SLC7A5-PGAM5 Interaction Promotes Advanced Atherosclerosis Through Hindering Mitochondrial Function of Macrophages.
Adv Sci (Weinh), 2025/11/21;:e18359.
Zhong S[1, 2, 3], Wang X[1, 2, 3], Li Q[4, 5], Wang S[1, 2, 3], Sun B[6], Ni W[2, 6, 7], Zhou G[1, 2, 3], Wang F[1, 2, 3], Xie X[1, 2, 3], Jin C[2], Xu G[8], Zhao P[1, 2, 3], Peng X[1, 2, 3], Han F[1, 2], Xi X[2, 9], Wang Y[1, 2], Xu J[8], Wang Y[4, 5, 10], Gu X[1, 2, 3, 11], Li S[1, 2], Zhang J[12], Li S[7, 13, 14], Tian J[1, 2, 3, 15, 16]
Affiliations
PMID: 41270215DOI: 10.1002/advs.202518359
Impact factor: 17.521
Abstract
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 CD5Lhi 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 Cd5lhi macrophages, highlighting it as a potential therapeutic target. Strategies aimed at improving mitochondrial function also offer a promising approach for advanced atherosclerosis treatment.
Keywords: PGAM5; SLC7A5; advanced atherosclerosis; leucine; macrophages; mitochondria
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