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Title: Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver disease
Author: Hernández-Alvarez, María Isabel
Sebastián Muñoz, David
Vives, Sara
Ivanova, Saska
Bartoccioni, Paola
Kakimoto, Pamela
Plana, Natalia
Veiga, Sonia R.
Hernandez, Vanessa
Vasconcelos, Nuno
Peddinti, Gopal
Adrover, Anna
Jove, Mariona
Pamplona, Reinald
Gordaliza-Alaguero, Isabel
Calvo, Enrique
Cabre, Noemí
Castro, Rui
Kuzmanic, Antonija
Boutant, Marie
Sala, David
Hyotylainen, Tuulia
Oresic, Matej
Fort i Baixeras, Joana
Errasti-Murugarren, Ekaitz
Rodrigues, CMP.
Orozco López, Modesto
Joven, Jorge
Cantó, Carles
Palacín Prieto, Manuel
Fernandez-Veledo, Sonia
Vendrell, Joan
Zorzano Olarte, Antonio
Keywords: Malalties del fetge
Proteïnes de membrana
Liver diseases
Membrane proteins
Issue Date: 2-May-2019
Publisher: Cell Press
Abstract: 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.
Note: Versió postprint del document publicat a:
It is part of: Cell, 2019, vol. 177, num. 4, p. 881-895
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ISSN: 0092-8674
Appears in Collections:Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))

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