Authors: María Isabel Hernández-Alvarez, David Sebastián, Sara Vives, Saška Ivanova, Paola Bartoccioni, Pamela Kakimoto, Natalia Plana, Sónia R. Veiga, Vanessa Hernández, Nuno Vasconcelos, Gopal Peddinti, Anna Adrover, Mariona Jové, Reinald Pamplona, Isabel Gordaliza-Alaguero, Enrique Calvo, Noemí Cabré, Rui Castro, Antonija Kuzmanic, Marie Boutant, David Sala, Tuulia Hyotylainen, Matej Orešič, Joana Fort, Ekaitz Errasti-Murugarren, Cecilia M.P. Rodrígues, Modesto Orozco, Jorge Joven, Carles Cantó, Manuel Palacin, Sonia Fernández-Veledo, Joan Vendrell, Antonio Zorzano
Summary: Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we showthat the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease.Reduced Mfn2 expression was detected in liver biopsies from patients with non-alcoholic steatohepatitis(NASH). Moreover, reduced Mfn2 levels were detected in mouse models of steatosis orNASH, and its re-expression in a NASH mouse model ameliorated the disease. Liver-specificablation of Mfn2 in mice provoked inflammation, triglyceride accumulation, fibrosis,and liver cancer. We demonstrate that Mfn2 binds phosphatidylserine (PS) and can specificallyextract PS into membrane domains, favoring PS transfer to mitochondria and mitochondrialphosphatidylethanolamine (PE) synthesis. Consequently, hepatic Mfn2 deficiency reducesPS transfer and phospholipid synthesis, leading to endoplasmic reticulum (ER) stressand the development of a NASH-like phenotype and liver cancer. Ablation of Mfn2 inliver reveals that disruption of ER-mitochondrial PS transfer is a new mechanism involvedin the development of liver disease.
Source: Cell, 2019; 177 (4): 881