LRP1 immunotherapy enhances cardiomyocyte respiration by restricting cholesteryl ester accumulation in mitochondria

Antibodies (Abs) targeting the P3 sequence (Gly1127-Cys1140) 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...

Descripción completa

Detalles Bibliográficos
Autores: Benitez-Amaro, A, Garcia, E, Lhoëst, MTL, Polishchuk, A, Zegri-Reiriz, I, Vilades, D, Guerra, JM, Fernández-del-Rio, L, Mirabet, S, Samouillan, V, Shirihai, O, Liesa, M, Enrich, C, Llorente-Cortés, V
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p19405
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=19405
Access Level:acceso abierto
Palabra clave:cholesteryl esters
heart
lipid droplets
LRP1
mitochondria
respirometry
id ES_d4e2ebab1a07067a3a2448fcbec01dcd
oai_identifier_str oai:iibsantpau.fundanetsuite.com:p19405
network_acronym_str ES
network_name_str España
repository_id_str
spelling LRP1 immunotherapy enhances cardiomyocyte respiration by restricting cholesteryl ester accumulation in mitochondriaBenitez-Amaro, AGarcia, ELhoëst, MTLPolishchuk, AZegri-Reiriz, IVilades, DGuerra, JMFernández-del-Rio, LMirabet, SSamouillan, VShirihai, OLiesa, MEnrich, CLlorente-Cortés, Vcholesteryl estersheartlipid dropletsLRP1mitochondriarespirometryAntibodies (Abs) targeting the P3 sequence (Gly1127-Cys1140) 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.AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=19405JOURNAL OF LIPID RESEARCHISSN: 00222275ISSNe: 15397262reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p194052026-06-14T12:41:47Z
dc.title.none.fl_str_mv LRP1 immunotherapy enhances cardiomyocyte respiration by restricting cholesteryl ester accumulation in mitochondria
title LRP1 immunotherapy enhances cardiomyocyte respiration by restricting cholesteryl ester accumulation in mitochondria
spellingShingle LRP1 immunotherapy enhances cardiomyocyte respiration by restricting cholesteryl ester accumulation in mitochondria
Benitez-Amaro, A
cholesteryl esters
heart
lipid droplets
LRP1
mitochondria
respirometry
title_short LRP1 immunotherapy enhances cardiomyocyte respiration by restricting cholesteryl ester accumulation in mitochondria
title_full LRP1 immunotherapy enhances cardiomyocyte respiration by restricting cholesteryl ester accumulation in mitochondria
title_fullStr LRP1 immunotherapy enhances cardiomyocyte respiration by restricting cholesteryl ester accumulation in mitochondria
title_full_unstemmed LRP1 immunotherapy enhances cardiomyocyte respiration by restricting cholesteryl ester accumulation in mitochondria
title_sort LRP1 immunotherapy enhances cardiomyocyte respiration by restricting cholesteryl ester accumulation in mitochondria
dc.creator.none.fl_str_mv Benitez-Amaro, A
Garcia, E
Lhoëst, MTL
Polishchuk, A
Zegri-Reiriz, I
Vilades, D
Guerra, JM
Fernández-del-Rio, L
Mirabet, S
Samouillan, V
Shirihai, O
Liesa, M
Enrich, C
Llorente-Cortés, V
author Benitez-Amaro, A
author_facet Benitez-Amaro, A
Garcia, E
Lhoëst, MTL
Polishchuk, A
Zegri-Reiriz, I
Vilades, D
Guerra, JM
Fernández-del-Rio, L
Mirabet, S
Samouillan, V
Shirihai, O
Liesa, M
Enrich, C
Llorente-Cortés, V
author_role author
author2 Garcia, E
Lhoëst, MTL
Polishchuk, A
Zegri-Reiriz, I
Vilades, D
Guerra, JM
Fernández-del-Rio, L
Mirabet, S
Samouillan, V
Shirihai, O
Liesa, M
Enrich, C
Llorente-Cortés, V
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv cholesteryl esters
heart
lipid droplets
LRP1
mitochondria
respirometry
topic cholesteryl esters
heart
lipid droplets
LRP1
mitochondria
respirometry
description Antibodies (Abs) targeting the P3 sequence (Gly1127-Cys1140) 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.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=19405
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=19405
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
publisher.none.fl_str_mv AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
dc.source.none.fl_str_mv JOURNAL OF LIPID RESEARCH
ISSN: 00222275
ISSNe: 15397262
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869420585822453760
score 15,81155

Similares en LA Referencia