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oai:recercat.cat:2445/1716472025-12-04T21:12:43Zcom_2072_1057col_2072_478781col_2072_478916col_2072_478908col_2072_478917

00925njm 22002777a 4500 dc Hernández-Alvarez, María Isabel author Sebastián Muñoz, David author Vives, Sara author Ivanova, Saška author Bartoccioni, Paola author Kakimoto, Pamela author Plana, Natalia author Veiga, Sonia Rosa Pereira da author Hernandez, Vanessa author Vasconcelos, Nuno author Peddinti, Gopal author Adrover, Anna author Jove, Mariona author Pamplona, Reinald author Gordaliza-Alaguero, Isabel author Calvo, Enrique author Cabre, Noemí author Castro, Rui author Kuzmanic, Antonija author Boutant, Marie author Sala, David author Hyotylainen, Tuulia author Oresic, Matej author Fort i Baixeras, Joana author Errasti-Murugarren, Ekaitz author Rodrigues, CMP. author Orozco López, Modesto author Joven, Jorge author Cantó, Carles author Palacín Prieto, Manuel author Fernandez-Veledo, Sonia author Vendrell, Joan author Zorzano Olarte, Antonio author 2020-11-03T08:55:50Z 2020-11-03T08:55:50Z 2019-05-02 2020-11-03T08:55:50Z Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we show that the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease. Reduced Mfn2 expression was detected in liver biopsies from patients with nonalcoholic steatohepatitis (NASH). Moreover, reduced Mfn2 levels were detected in mouse models of steatosis or NASH, and its re-expression in a NASH mouse model ameliorated the disease. Liver-specific ablation of Mfn2 in mice provoked inflammation, triglyceride accumulation, fibrosis, and liver cancer. We demonstrate that Mfn2 binds phosphatidylserine (PS) and can specifically extract PS into membrane domains, favoring PS transfer to mitochondria and mitochondrial phosphatidylethanolamine (PE) synthesis. Consequently, hepatic Mfn2 deficiency reduces PS transfer and phospholipid synthesis, leading to endoplasmic reticulum (ER) stress and the development of a NASH-like phenotype and liver cancer. Ablation of Mfn2 in liver reveals that disruption of ER-mitochondrial PS transfer is a new mechanism involved in the development of liver disease. Malalties del fetge Proteïnes de membrana Mitocondris Liver diseases Membrane proteins Mitochondria Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver disease