Leucine‐Dependent SLC7A5–PGAM5 Interaction Promotes Advanced Atherosclerosis Through Hindering Mitochondrial Function of Macrophages
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<sup>hi</sup> 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<sup>hi</sup> macrophages, highlighting it as a potential therapeutic target. Strategies aimed at improving mitochondrial function also offer a promising approach for advanced atherosclerosis treatment.
Authors
- Xueyu Wang (ORCID: https://orcid.org/0000-0002-5301-0216)
- Xiang Peng (ORCID: https://orcid.org/0000-0003-3453-4062)
- Wenjun Ni (ORCID: https://orcid.org/0000-0002-0770-8568)
- Xianwei Xie (ORCID: https://orcid.org/0000-0002-0896-1418)
- Shuijie Li (ORCID: https://orcid.org/0000-0003-4538-8996)
- Bin Sun (ORCID: https://orcid.org/0000-0001-5983-7436)
- Jin Cheng (ORCID: https://orcid.org/0000-0001-7041-8283)
- Guozhong Zhou (ORCID: https://orcid.org/0009-0001-9112-6631)
- Shan Zhong (ORCID: https://orcid.org/0000-0003-3220-3980)
- Feiyuan Han (ORCID: https://orcid.org/0000-0002-5044-7842)
- Peng Zhao (ORCID: https://orcid.org/0000-0001-6216-3858)
- Xiangwen Xi (ORCID: https://orcid.org/0000-0003-4425-9404)
- Yue Wang (ORCID: https://orcid.org/0000-0003-2103-4237)
- Fan Wang (ORCID: https://orcid.org/0000-0001-9806-5037)
- Shuo Li (ORCID: https://orcid.org/0000-0003-2686-4934)
- Jian Zhang (ORCID: https://orcid.org/0000-0001-5160-5550)
- Siqi Wang (ORCID: https://orcid.org/0000-0002-1491-2962)
- Yidan Wang (ORCID: https://orcid.org/0000-0002-0952-5386)
- Qingsong Li (ORCID: https://orcid.org/0000-0003-1425-8822)
- Jinwei Tian (ORCID: https://orcid.org/0000-0002-2730-0033)
- Juan Xu
- Xia Gu (ORCID: https://orcid.org/0009-0003-8259-2934)
- Gang Xu (ORCID: https://orcid.org/0000-0002-8136-9277)
Institutions
- East China University of Science and Technology (CN)
- Harbin Engineering University (CN)
- Harbin Medical University (CN)
- Shanxi Medical University (CN)
- University of Macau (MO)
- Beijing Graphene Institute (CN)
- Heilongjiang Provincial Hospital (CN)
- Second Affiliated Hospital of Harbin Medical University (CN)
- Education Department of Heilongjiang Province (CN)
- Hainan Medical University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-11-21
- DOI
- https://doi.org/10.1002/advs.202518359
- Primary Topic
- Muscle metabolism and nutrition
- Type
- article
- Field-Weighted Citation Impact
- 0.00