# Leucine‐Dependent SLC7A5–PGAM5 Interaction Promotes Advanced Atherosclerosis Through Hindering Mitochondrial Function of Macrophages

## TL;DR

Leucine promotes advanced atherosclerosis by impairing macrophage mitochondrial function, and reducing leucine intake may help treat the disease.

## Contribution

The study reveals a novel mechanism by which leucine influences atherosclerosis through SLC7A5–PGAM5 interactions and mitochondrial function in macrophages.

## Key findings

- Leucine deprivation improves mitochondrial function in macrophages and reduces atherosclerosis in mice.
- Reduced SLC7A5–PGAM5 binding promotes PGAM5–NDUFV1 interaction, enhancing mitochondrial activity.
- Higher plasma leucine levels correlate with increased risk of myocardial infarction.

## 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 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.

Higher plasma leucine is associated with increased risk of new‐onset myocardial infarction. Leucine deprivation alleviates advanced atherosclerosis in mice. Tumor‐induced leucine deprivation reprograms macrophage metabolism and increases CD5Lhi macrophages in mouse plaques. Mechanistically, leucine deficiency reduced SLC7A5‐PGAM5 binding in macrophages, promoting PGAM5‐NDUFV1 interaction and enhancing mitochondrial function, which attenuates atherosclerosis progression.