Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease

TitleDeficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease
Publication TypeJournal Article
Year of Publication2019
AuthorsHernández-Alvarez, María Isabel, Sebastián David, Vives Sara, Ivanova Saška, Bartoccioni Paola, Kakimoto Pamela, Plana Natalia, Veiga Sónia R., Hernández Vanessa, Vasconcelos Nuno, Peddinti Gopal, Adrover Anna, Jové Mariona, Pamplona Reinald, Gordaliza-Alaguero Isabel, Calvo Enrique, Cabré Noemí, Castro Rui, Kuzmanic Antonija, Boutant Marie, Sala David, Hyotylainen Tuulia, Orešič Matej, Fort Joana, Errasti-Murugarren Ekaitz, Rodrígues Cecilia M. P., Orozco Modesto, Joven Jorge, Cantó Carles, Palacín Manuel, Fernández-Veledo Sonia, Vendrell Joan, and Zorzano Antonio
JournalCell
Volume177
Issue4
Pagination881 - 895.e17
Date Published05/2019
ISBN Number0092-8674
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 non-alcoholic 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.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 non-alcoholic 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.

URLhttps://doi.org/10.1016/j.cell.2019.04.010
Highlight: 
Review: