Fuertes-Agudo 2022 Antioxidants (Basel)

Fuertes-Agudo M, Luque-Tévar M, Cucarella C, Brea R, Boscá L, Quintana-Cabrera R, Martín-Sanz P, Casado M (2022) COX-2 expression in hepatocytes improves mitochondrial function after hepatic ischemia-reperfusion injury.

» Antioxidants (Basel) 11:1724. PMID: 36139798 Open Access

Fuertes-Agudo Marina,  Luque-Tevar Maria,  Cucarella Carme,  Brea Rocio,  Bosca Lisardo,  Quintana-Cabrera Ruben,  Martin-Sanz Paloma,  Casado Marta (2022) Antioxidants (Basel)

Abstract: 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. • Keywords: COX-2, High-resolution respirometry, Ischemia-reperfusion, Liver, Mitochondrial dynamics, Prostaglandins • Bioblast editor: Plangger M • O2k-Network Lab: ES Valencia Casado Pinna M

Labels: MiParea: Respiration, Genetic knockout;overexpression 

Stress:Ischemia-reperfusion  Organism: Mouse  Tissue;cell: Liver  Preparation: Isolated mitochondria 

Coupling state: OXPHOS, ET  Pathway: F, N, Gp, CIV, NS, Other combinations, ROX  HRR: Oxygraph-2k 

2022-11