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COX-2 Expression in Hepatocytes Improves Mitochondrial Function after Hepatic Ischemia-Reperfusion Injury

Cyclooxygenase 2 (COX-2) is a key enzyme in prostanoid biosynthesis. The constitutive hepatocyte expression of COX-2 has a protective role in hepatic ischemia-reperfusion (I/R) injury (IRI), decreasing necrosis, reducing reactive oxygen species (ROS) levels, and increasing autophagy and antioxidant...

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Autores principales: Fuertes-Agudo, Marina, Luque-Tévar, María, Cucarella, Carme, Brea, Rocío, Boscá, Lisardo, Quintana-Cabrera, Rubén, Martín-Sanz, Paloma, Casado, Marta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9495319/
https://www.ncbi.nlm.nih.gov/pubmed/36139798
http://dx.doi.org/10.3390/antiox11091724
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author Fuertes-Agudo, Marina
Luque-Tévar, María
Cucarella, Carme
Brea, Rocío
Boscá, Lisardo
Quintana-Cabrera, Rubén
Martín-Sanz, Paloma
Casado, Marta
author_facet Fuertes-Agudo, Marina
Luque-Tévar, María
Cucarella, Carme
Brea, Rocío
Boscá, Lisardo
Quintana-Cabrera, Rubén
Martín-Sanz, Paloma
Casado, Marta
author_sort Fuertes-Agudo, Marina
collection PubMed
description Cyclooxygenase 2 (COX-2) is a key enzyme in prostanoid biosynthesis. The constitutive hepatocyte expression of COX-2 has a protective role in hepatic ischemia-reperfusion (I/R) injury (IRI), decreasing necrosis, reducing reactive oxygen species (ROS) levels, and increasing autophagy and antioxidant and anti-inflammatory response. The physiopathology of IRI directly impacts mitochondrial activity, causing ATP depletion and being the main source of ROS. Using genetically modified mice expressing human COX-2 (h-COX-2 Tg) specifically in hepatocytes, and performing I/R surgery on the liver, we demonstrate that COX-2 expression has a beneficial effect at the mitochondrial level. Mitochondria derived from h-COX-2 Tg mice livers have an increased respiratory rate associated with complex I electron-feeding pathways compared to Wild-type (Wt) littermates, without affecting complex I expression or assembly. Furthermore, Wt-derived mitochondria show a loss of mitochondrial membrane potential (ΔΨm) that correlates to increased proteolysis of fusion-related OPA1 through OMA1 protease activity. All these effects are not observed in h-COX-2 Tg mitochondria, which behave similarly to the Sham condition. These results suggest that COX-2 attenuates IRI at a mitochondrial level, preserving the proteolytic processing of OPA1, in addition to the maintenance of mitochondrial respiration.
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spelling pubmed-94953192022-09-23 COX-2 Expression in Hepatocytes Improves Mitochondrial Function after Hepatic Ischemia-Reperfusion Injury Fuertes-Agudo, Marina Luque-Tévar, María Cucarella, Carme Brea, Rocío Boscá, Lisardo Quintana-Cabrera, Rubén Martín-Sanz, Paloma Casado, Marta Antioxidants (Basel) Article Cyclooxygenase 2 (COX-2) is a key enzyme in prostanoid biosynthesis. The constitutive hepatocyte expression of COX-2 has a protective role in hepatic ischemia-reperfusion (I/R) injury (IRI), decreasing necrosis, reducing reactive oxygen species (ROS) levels, and increasing autophagy and antioxidant and anti-inflammatory response. The physiopathology of IRI directly impacts mitochondrial activity, causing ATP depletion and being the main source of ROS. Using genetically modified mice expressing human COX-2 (h-COX-2 Tg) specifically in hepatocytes, and performing I/R surgery on the liver, we demonstrate that COX-2 expression has a beneficial effect at the mitochondrial level. Mitochondria derived from h-COX-2 Tg mice livers have an increased respiratory rate associated with complex I electron-feeding pathways compared to Wild-type (Wt) littermates, without affecting complex I expression or assembly. Furthermore, Wt-derived mitochondria show a loss of mitochondrial membrane potential (ΔΨm) that correlates to increased proteolysis of fusion-related OPA1 through OMA1 protease activity. All these effects are not observed in h-COX-2 Tg mitochondria, which behave similarly to the Sham condition. These results suggest that COX-2 attenuates IRI at a mitochondrial level, preserving the proteolytic processing of OPA1, in addition to the maintenance of mitochondrial respiration. MDPI 2022-08-30 /pmc/articles/PMC9495319/ /pubmed/36139798 http://dx.doi.org/10.3390/antiox11091724 Text en © 2022 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
Fuertes-Agudo, Marina
Luque-Tévar, María
Cucarella, Carme
Brea, Rocío
Boscá, Lisardo
Quintana-Cabrera, Rubén
Martín-Sanz, Paloma
Casado, Marta
COX-2 Expression in Hepatocytes Improves Mitochondrial Function after Hepatic Ischemia-Reperfusion Injury
title COX-2 Expression in Hepatocytes Improves Mitochondrial Function after Hepatic Ischemia-Reperfusion Injury
title_full COX-2 Expression in Hepatocytes Improves Mitochondrial Function after Hepatic Ischemia-Reperfusion Injury
title_fullStr COX-2 Expression in Hepatocytes Improves Mitochondrial Function after Hepatic Ischemia-Reperfusion Injury
title_full_unstemmed COX-2 Expression in Hepatocytes Improves Mitochondrial Function after Hepatic Ischemia-Reperfusion Injury
title_short COX-2 Expression in Hepatocytes Improves Mitochondrial Function after Hepatic Ischemia-Reperfusion Injury
title_sort cox-2 expression in hepatocytes improves mitochondrial function after hepatic ischemia-reperfusion injury
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9495319/
https://www.ncbi.nlm.nih.gov/pubmed/36139798
http://dx.doi.org/10.3390/antiox11091724
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