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MCJ: A therapeutic target in hepatic ischemia and reperfusion injury

AuthorsGoikoetxea, Naroa; Fernandez Ramos, David; Serrano-Macia M.; Eugenia Cornide, Maria; Jimenez-Castro, Monica; Alfano, Bennedetta; Saenz de Urturi, Diego; Gonzalez-Romero, Francisco; Gutiérrez de Juan, Virginia; Rodriguez Iruretagoyena, Begoña; Cardoso Delgado, Teresa; Lopitz-Otsoa, Fernando; Barbier Torres, Lucia; Fernández-Tussy P.; Simon, Jorge; Martín, Paloma ; Anguita, Juan; Perez Redondo, Marina; Miñambres, Eduardo; Lu, Shelly C.; Mato, José M.; Sabio, Guadalupe; Peralta, Carmen; Aspichueta, Patricia; Casado, Marta ; Martin, Cesar; Varela-Rey M.; Luz Martinez-Chantar, Maria
Issue Date10-Apr-2019
CitationThe International Liver Congress (2019)
Abstract[Background and aims]: Ischemia/reperfusion (IR) injury, a frequent pathological process during liver resection, is a leading cause of post transplantation organ dysfunction. The extent of the injury can determine the success of the procedure and the survival of the patient. Therefore, attenuation of pathology caused by the injury and improving liver function after the procedure would be critical for clinicians to diminish IR injury prevalence and improve the outcome. Mitochondria play a key role in liver homeostasis; indeed, more functional mitochondria induce hepatic regeneration. MCJ, also known as DNACJ15, is an endogenous negative regulator of complex I, located in the mitochondrial electron transport chain. While under normal conditions MCJ deficiency does not result in an altered phenotype in mice, its absence improves mitochondrial activity without increasing mitochondrial ROS. We present MCJ as a new target to minimize hepatic damage caused by IR injury and enhance the efficiency of liver regeneration during liver resection.
[Method]: Partial hepatectomies (PH) and PH combined with IR injuries were performed in MCJ-KO mice and in WT mice after MCJ silencing.
[Results]: We observed that the lack of MCJ reduced liver damage and induced hepatic regeneration after IR injury; MCJ-KO mice showed lower levels of Caspase 3 and a significantly higher Cyclin D1 expression. Moreover, we saw an improved metabolic response to hepatic insufficiency and an accelerated cell cycle progression during liver resection, which led to a faster recovery of the hepatic mass. In the initial phase after the PH, glucagon response was amplified in MCJ-KO mice, characterized by increased cAMP and AKT signaling, along with higher Ca+2 release from the endoplasmic reticulum (ER), glycogen synthase kinase (GSK-3beta) inhibition and nuclear factorKbeta (NFKbeta) translocation to the nucleus. In the proliferative phase, ablation of MCJ accelerated the induction of proliferative markers. Indeed, after MCJ silencing, an improved phenotype was detected in an aging mice model that underwent partial hepatectomy. Hepatic insufficiency was ameliorated, PCNA expression increased and steatosis reverted. Importantly, the combined procedure of PH and IR injury that resemble liver transplant procedure resulted in a 100% survival rate for MCJ-KO mice while just the 33% of MCJ-WT mice survived the operation. Increased levels of MCJ were found in liver biopsies from all liver donors at 60 minutes after normothermic regional perfusion (nRP) was started.
[Conclusion]: Overall, MCJ silencing during liver resection emerges as a promising therapy for IR injury and restoration of hepatic mass.
DescriptionTrabajo presentado en The International Liver Congress, celebrado en Viena (Austria) del 10 al 14 de abril de 2019.
Publisher version (URL)http://dx.doi.org/10.1016/S0618-8278(19)30040-4
Identifiersdoi: 10.1016/S0618-8278(19)30040-4
Appears in Collections:(UBF) Comunicaciones congresos
(IBV) Comunicaciones congresos
(IIBM) Comunicaciones congresos
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