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

Shan Zhong; Xueyu Wang; Qingsong Li; Siqi Wang; Bin Sun; Wenjun Ni; Gengyu Zhou; Fan Wang; Xianwei Xie; Cheng Jin; Gang Xu; Peng Zhao; Xiang Peng; Feiyuan Han; Xiangwen Xi; Yidan Wang; Juan Xu; Yue Wang; Xia Gu; Shuo Li; Jian Zhang; Shuijie Li; Jinwei Tian

doi:10.1002/advs.202518359

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

Adv Sci (Weinh). 2026 Feb;13(7):e18359. doi: 10.1002/advs.202518359. Epub 2025 Nov 21.

Authors

Shan Zhong^{1

2

3}, Xueyu Wang^{1

2

3}, Qingsong Li^{4

5}, Siqi Wang^{1

2

3}, Bin Sun⁶, Wenjun Ni^{2

6

7}, Gengyu Zhou^{1

2

3}, Fan Wang^{1

2

3}, Xianwei Xie^{1

2

3}, Cheng Jin², Gang Xu⁸, Peng Zhao^{1

2

3}, Xiang Peng^{1

2

3}, Feiyuan Han^{1

2}, Xiangwen Xi^{2

9}, Yidan Wang^{1

2}, Juan Xu⁸, Yue Wang^{4

5

10}, Xia Gu^{1

2

3

11}, Shuo Li^{1

2}, Jian Zhang¹², Shuijie Li^{7

13

14}, Jinwei Tian^{1

2

3

15

16}

Affiliations

¹ Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, P. R. China.
² Heilongjiang Provincial Key Laboratory of Panvascular Disease, Harbin, 150081, P. R. China.
³ The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, 150001, P. R. China.
⁴ BGI Research, Beijing, 102601, P. R. China.
⁵ Collaborative Innovation Center for Molecular Imaging of Precision Medicine, Shanxi Medical University, Taiyuan, Shanxi, 030001, P. R. China.
⁶ Research Center for Pharmacoinformatics (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, Harbin, 150081, P. R. China.
⁷ College of Pharmacy, Harbin Medical University, Harbin, 150081, P. R. China.
⁸ College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, 150081, P. R. China.
⁹ Department of Cardiology, the Second Affiliated Hospital of Hainan Medical University, Haikou, 570311, P. R. China.
¹⁰ State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, P. R. China.
¹¹ Cardiovascular Imaging Center, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, P. R. China.
¹² School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, P. R. China.
¹³ Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Harbin, 150081, P. R. China.
¹⁴ Heilongjiang Province Key Laboratory of Research on Molecular Targeted Anti-Tumor Drugs, Harbin, 150000.
¹⁵ State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Harbin Medical University, Harbin, 150081, P. R. China.
¹⁶ Department of Geriatrics, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, P. R. China.

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 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.

Keywords: PGAM5; SLC7A5; advanced atherosclerosis; leucine; macrophages; mitochondria.

MeSH terms

Animals
Atherosclerosis* / genetics
Atherosclerosis* / metabolism
Atherosclerosis* / pathology
Disease Models, Animal
Humans
Large Neutral Amino Acid-Transporter 1* / genetics
Large Neutral Amino Acid-Transporter 1* / metabolism
Leucine* / metabolism
Macrophages* / metabolism
Male
Mice
Mice, Inbred C57BL
Mitochondria* / metabolism

Substances

Leucine
Large Neutral Amino Acid-Transporter 1

Abstract

MeSH terms

Substances

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