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

18 páginas, 7 figurasCyclooxygenase 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.The experiments were performed in laboratories where projects are supported by: Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación 10.13039/501100011033 (SAF2016- 75004-R and PID2019-108977RB-I00), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CB06/04/1069), Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CB/11/00222), Consorcio de Investigación en Red de la Comunidad de Madrid, S2017/BMD-3686,and Fondo Europeo de Desarrollo Regional. M.F.-A. and M.L.-T. are recipient of FPI fellowship from MINECO (BES-2017-081928 and PRE2020-094885, respectively).Peer reviewe