Article Impact Level: HIGH Data Quality: STRONG Summary of Journal of Lipid Research, 66(5), 100783. https://doi.org/10.1016/j.jlr.2025.100783 Dr. Aleyda Benitez-Amaro et al.
Points
- A high-fat, high-cholesterol diet leads to cholesteryl ester accumulation in cardiomyocyte mitochondria, impairing bioenergetics and promoting dysfunction through LDL receptor-related protein 1 transport.
- Anti-P3 antibodies target LRP1 to block CE uptake, significantly reducing mitochondrial and lipid droplet CE accumulation in a rabbit model with human-like lipid profiles.
- Treatment with anti-P3 antibodies restores mitochondrial cristae, improves oxidative phosphorylation efficiency, and normalizes ATP production, particularly enhancing complex II and IV activity.
- Enhanced interactions between mitochondria and lipid droplets were observed after treatment, with larger lipid droplet diameters and increased electrodensity indicating structural and functional recovery.
- These findings suggest anti-P3 antibodies could offer a novel therapeutic strategy to reverse cholesterol-induced mitochondrial dysfunction in conditions like obesity, hypercholesterolemia, and ischemic heart disease.
Summary
This study explores the impact of cholesterol accumulation in cardiomyocyte mitochondria and the potential of anti-P3 antibodies in reversing mitochondrial dysfunction induced by a high-fat, high-cholesterol (HFHC) diet. Using a rabbit model with a lipid profile similar to humans, researchers investigated the LDL receptor-related protein 1 (LRP1) role in transporting cholesteryl esters (CE) into cardiomyocytes, where they accumulate in mitochondria and disrupt mitochondrial function. Subcellular fractionation revealed that HFHC induced CE accumulation in mitochondria, significantly impairing cardiac bioenergetics, which was alleviated by anti-P3 antibodies targeting LRP1.
The results showed that treatment with anti-P3 antibodies effectively reduced CE accumulation in mitochondria and lipid droplets (LDs), improving mitochondrial structure and function. Transmission electron microscopy demonstrated restoration of mitochondrial cristae, essential for oxidative phosphorylation. Additionally, mitochondrial respiratory capacity, assessed by Seahorse analysis, was significantly improved by anti-P3 treatment, which normalized ATP production and enhanced oxidative phosphorylation efficiency, specifically restoring complex II/IV activity. Notably, anti-P3 antibodies promoted more extensive interactions between mitochondria and LDs, resulting in larger LD diameters and increased electrodensity.
This study highlights the therapeutic potential of anti-P3 antibodies in mitigating cholesterol-induced mitochondrial dysfunction in cardiomyocytes. By blocking CE uptake from lipoproteins, this approach restores mitochondrial architecture and bioenergetics, offering a novel strategy for treating cardiovascular diseases associated with altered lipid metabolism, such as hypercholesterolemia, obesity, and myocardial ischemia. These findings open new avenues for therapeutic interventions to preserve mitochondrial function and protect the heart from the bioenergetic dysfunction that precedes heart failure.
Link to the article: https://www.jlr.org/article/S0022-2275(25)00043-4/fulltext
References Benitez-Amaro, A., Garcia, E., LaChica Lhoëst, M. T., Polishchuk, A., Zegri-Reiriz, I., Vilades, D., Guerra, J. M., Fernández-del-Rio, L., Mirabet, S., Samouillan, V., Shirihai, O., Liesa, M., Enrich, C., & Llorente-Cortés, V. (2025). LRP1 immunotherapy enhances cardiomyocyte respiration by restricting cholesteryl ester accumulation in mitochondria. Journal of Lipid Research, 66(5), 100783. https://doi.org/10.1016/j.jlr.2025.100783
