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Palmitate-Induced Cardiac Lipotoxicity Is Relieved by the Redox-Active Motif of SELENOT through Improving Mitochondrial Function and Regulating Metabolic State

Cardiac lipotoxicity is an important contributor to cardiovascular complications during obesity. Given the fundamental role of the endoplasmic reticulum (ER)-resident Selenoprotein T (SELENOT) for cardiomyocyte differentiation and protection and for the regulation of glucose metabolism, we took adva...

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Autores principales: Rocca, Carmine, De Bartolo, Anna, Guzzi, Rita, Crocco, Maria Caterina, Rago, Vittoria, Romeo, Naomi, Perrotta, Ida, De Francesco, Ernestina Marianna, Muoio, Maria Grazia, Granieri, Maria Concetta, Pasqua, Teresa, Mazza, Rosa, Boukhzar, Loubna, Lefranc, Benjamin, Leprince, Jérôme, Gallo Cantafio, Maria Eugenia, Soda, Teresa, Amodio, Nicola, Anouar, Youssef, Angelone, Tommaso
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093731/
https://www.ncbi.nlm.nih.gov/pubmed/37048116
http://dx.doi.org/10.3390/cells12071042
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author Rocca, Carmine
De Bartolo, Anna
Guzzi, Rita
Crocco, Maria Caterina
Rago, Vittoria
Romeo, Naomi
Perrotta, Ida
De Francesco, Ernestina Marianna
Muoio, Maria Grazia
Granieri, Maria Concetta
Pasqua, Teresa
Mazza, Rosa
Boukhzar, Loubna
Lefranc, Benjamin
Leprince, Jérôme
Gallo Cantafio, Maria Eugenia
Soda, Teresa
Amodio, Nicola
Anouar, Youssef
Angelone, Tommaso
author_facet Rocca, Carmine
De Bartolo, Anna
Guzzi, Rita
Crocco, Maria Caterina
Rago, Vittoria
Romeo, Naomi
Perrotta, Ida
De Francesco, Ernestina Marianna
Muoio, Maria Grazia
Granieri, Maria Concetta
Pasqua, Teresa
Mazza, Rosa
Boukhzar, Loubna
Lefranc, Benjamin
Leprince, Jérôme
Gallo Cantafio, Maria Eugenia
Soda, Teresa
Amodio, Nicola
Anouar, Youssef
Angelone, Tommaso
author_sort Rocca, Carmine
collection PubMed
description Cardiac lipotoxicity is an important contributor to cardiovascular complications during obesity. Given the fundamental role of the endoplasmic reticulum (ER)-resident Selenoprotein T (SELENOT) for cardiomyocyte differentiation and protection and for the regulation of glucose metabolism, we took advantage of a small peptide (PSELT), derived from the SELENOT redox-active motif, to uncover the mechanisms through which PSELT could protect cardiomyocytes against lipotoxicity. To this aim, we modeled cardiac lipotoxicity by exposing H9c2 cardiomyocytes to palmitate (PA). The results showed that PSELT counteracted PA-induced cell death, lactate dehydrogenase release, and the accumulation of intracellular lipid droplets, while an inert form of the peptide (I-PSELT) lacking selenocysteine was not active against PA-induced cardiomyocyte death. Mechanistically, PSELT counteracted PA-induced cytosolic and mitochondrial oxidative stress and rescued SELENOT expression that was downregulated by PA through FAT/CD36 (cluster of differentiation 36/fatty acid translocase), the main transporter of fatty acids in the heart. Immunofluorescence analysis indicated that PSELT also relieved the PA-dependent increase in CD36 expression, while in SELENOT-deficient cardiomyocytes, PA exacerbated cell death, which was not mitigated by exogenous PSELT. On the other hand, PSELT improved mitochondrial respiration during PA treatment and regulated mitochondrial biogenesis and dynamics, preventing the PA-provoked decrease in PGC1-α and increase in DRP-1 and OPA-1. These findings were corroborated by transmission electron microscopy (TEM), revealing that PSELT improved the cardiomyocyte and mitochondrial ultrastructures and restored the ER network. Spectroscopic characterization indicated that PSELT significantly attenuated infrared spectral-related macromolecular changes (i.e., content of lipids, proteins, nucleic acids, and carbohydrates) and also prevented the decrease in membrane fluidity induced by PA. Our findings further delineate the biological significance of SELENOT in cardiomyocytes and indicate the potential of its mimetic PSELT as a protective agent for counteracting cardiac lipotoxicity.
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spelling pubmed-100937312023-04-13 Palmitate-Induced Cardiac Lipotoxicity Is Relieved by the Redox-Active Motif of SELENOT through Improving Mitochondrial Function and Regulating Metabolic State Rocca, Carmine De Bartolo, Anna Guzzi, Rita Crocco, Maria Caterina Rago, Vittoria Romeo, Naomi Perrotta, Ida De Francesco, Ernestina Marianna Muoio, Maria Grazia Granieri, Maria Concetta Pasqua, Teresa Mazza, Rosa Boukhzar, Loubna Lefranc, Benjamin Leprince, Jérôme Gallo Cantafio, Maria Eugenia Soda, Teresa Amodio, Nicola Anouar, Youssef Angelone, Tommaso Cells Article Cardiac lipotoxicity is an important contributor to cardiovascular complications during obesity. Given the fundamental role of the endoplasmic reticulum (ER)-resident Selenoprotein T (SELENOT) for cardiomyocyte differentiation and protection and for the regulation of glucose metabolism, we took advantage of a small peptide (PSELT), derived from the SELENOT redox-active motif, to uncover the mechanisms through which PSELT could protect cardiomyocytes against lipotoxicity. To this aim, we modeled cardiac lipotoxicity by exposing H9c2 cardiomyocytes to palmitate (PA). The results showed that PSELT counteracted PA-induced cell death, lactate dehydrogenase release, and the accumulation of intracellular lipid droplets, while an inert form of the peptide (I-PSELT) lacking selenocysteine was not active against PA-induced cardiomyocyte death. Mechanistically, PSELT counteracted PA-induced cytosolic and mitochondrial oxidative stress and rescued SELENOT expression that was downregulated by PA through FAT/CD36 (cluster of differentiation 36/fatty acid translocase), the main transporter of fatty acids in the heart. Immunofluorescence analysis indicated that PSELT also relieved the PA-dependent increase in CD36 expression, while in SELENOT-deficient cardiomyocytes, PA exacerbated cell death, which was not mitigated by exogenous PSELT. On the other hand, PSELT improved mitochondrial respiration during PA treatment and regulated mitochondrial biogenesis and dynamics, preventing the PA-provoked decrease in PGC1-α and increase in DRP-1 and OPA-1. These findings were corroborated by transmission electron microscopy (TEM), revealing that PSELT improved the cardiomyocyte and mitochondrial ultrastructures and restored the ER network. Spectroscopic characterization indicated that PSELT significantly attenuated infrared spectral-related macromolecular changes (i.e., content of lipids, proteins, nucleic acids, and carbohydrates) and also prevented the decrease in membrane fluidity induced by PA. Our findings further delineate the biological significance of SELENOT in cardiomyocytes and indicate the potential of its mimetic PSELT as a protective agent for counteracting cardiac lipotoxicity. MDPI 2023-03-29 /pmc/articles/PMC10093731/ /pubmed/37048116 http://dx.doi.org/10.3390/cells12071042 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rocca, Carmine
De Bartolo, Anna
Guzzi, Rita
Crocco, Maria Caterina
Rago, Vittoria
Romeo, Naomi
Perrotta, Ida
De Francesco, Ernestina Marianna
Muoio, Maria Grazia
Granieri, Maria Concetta
Pasqua, Teresa
Mazza, Rosa
Boukhzar, Loubna
Lefranc, Benjamin
Leprince, Jérôme
Gallo Cantafio, Maria Eugenia
Soda, Teresa
Amodio, Nicola
Anouar, Youssef
Angelone, Tommaso
Palmitate-Induced Cardiac Lipotoxicity Is Relieved by the Redox-Active Motif of SELENOT through Improving Mitochondrial Function and Regulating Metabolic State
title Palmitate-Induced Cardiac Lipotoxicity Is Relieved by the Redox-Active Motif of SELENOT through Improving Mitochondrial Function and Regulating Metabolic State
title_full Palmitate-Induced Cardiac Lipotoxicity Is Relieved by the Redox-Active Motif of SELENOT through Improving Mitochondrial Function and Regulating Metabolic State
title_fullStr Palmitate-Induced Cardiac Lipotoxicity Is Relieved by the Redox-Active Motif of SELENOT through Improving Mitochondrial Function and Regulating Metabolic State
title_full_unstemmed Palmitate-Induced Cardiac Lipotoxicity Is Relieved by the Redox-Active Motif of SELENOT through Improving Mitochondrial Function and Regulating Metabolic State
title_short Palmitate-Induced Cardiac Lipotoxicity Is Relieved by the Redox-Active Motif of SELENOT through Improving Mitochondrial Function and Regulating Metabolic State
title_sort palmitate-induced cardiac lipotoxicity is relieved by the redox-active motif of selenot through improving mitochondrial function and regulating metabolic state
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093731/
https://www.ncbi.nlm.nih.gov/pubmed/37048116
http://dx.doi.org/10.3390/cells12071042
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