LRP1 immunotherapy enhances cardiomyocyte respiration by restricting cholesteryl ester accumulation in mitochondria
Benitez Amaro, Aleyda (Institut de Recerca Sant Pau)
Garcia, E. (Institut de Recerca Sant Pau)
LaChica Lhoëst, M.T. (Institut de Recerca Sant Pau)
Polishchuk, A. (Institut de Recerca Sant Pau)
Zegri-Reiriz, Isabel (Institut de Recerca Sant Pau)
Vilades, D. (Institut de Recerca Sant Pau)
Guerra, J.M. (Institut de Recerca Sant Pau)
Fernández-del-Rio, L. (University of California)
Mirabet, S. (Institut de Recerca Sant Pau)
Samouillan, V. (Universite de Toulouse)
Shirihai, Orion S (University of California)
Liesa, M. (Institut de Biologia Molecular de Barcelona)
Enrich, C. (Universitat de Barcelona)
Llorente-Cortés, V. (Institut de Recerca Sant Pau)

Data:	2025
Resum:	Antibodies (Abs) targeting the P3 sequence (Gly 1127 -Cys 1140) of LDL receptor-related protein 1 (anti-P3 Abs) inhibit the interaction between ApoB100 in cholesteryl ester (CE)-enriched lipoproteins and the CR9 domain in LDL receptor-related protein 1, preventing intracellular CE accumulation induced by a high-fat high-cholesterol (HFHC) diet in cardiomyocytes. This study examines (i) whether HFHC induces cholesterol accumulation in mitochondria, and impacts cardiac bioenergetics, and (ii) the effectiveness of anti-P3 Abs in mitigating HFHC-induced mitochondrial alterations. Cardiac tissue was homogenized, and mitochondria were isolated through subcellular fractionation. Thin layer chromatography demonstrated that HFHC induced the accumulation of CE in cardiac mitochondria, and that this process was significantly reduced by anti-P3 Abs. In line, transmission electron microscopy studies revealed that morphological changes induced by HFHC in cardiomyocyte mitochondria were reversed, at least in part, by anti-P3 Abs. Additionally, anti-P3 Abs promoted more extensive interactions between mitochondria and lipid droplets (LDs), accompanied by an increase in LD diameter and electrodensity in cardiomyocytes. Cardiac mitochondrial respiratory capacity assessed by Seahorse analysis showed that HFHC reduced CI/CIV and CII/CIV activity ratios, while anti-P3 Abs restored complex II/IV activity. In conclusion, by blocking CE uptake from lipoproteins, anti-P3 Abs reduce CE accumulation in the cardiomyocyte mitochondria and LDs, enhance bioenergetically favorable mitochondria/LD interactions, and improve cardiomyocyte respiratory function in hypercholesterolemic rabbits. These findings highlight the therapeutic potential of anti-P3 Abs in metabolic diseases by limiting CE loading of mitochondria and LDs in the heart and restoring cardiac bioenergetics.
Ajuts:	Instituto de Salud Carlos III PI21/01523 Instituto de Salud Carlos III PI24/00618 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-00834
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Cholesteryl esters ; Heart ; Lipid droplets ; LRP1 ; Mitochondria ; Respirometry
Publicat a:	Journal of Lipid Research, Vol. 66 Núm. 5 (May 2025) , ISSN 1539-7262

DOI: 10.1016/j.jlr.2025.100783
PMID: 40122209

17 p, 5.0 MB

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