Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes 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...

Descripción completa

Detalles Bibliográficos
Autores: Hernández-Alvarez, María Isabel, Sebastián, David, Vives, Sara, Ivanova, Sa ka, Bartoccioni, Paola, Kakimoto, Pamela, Plana, Natalia, Veiga, Sónia R., Hernández, Vanessa, Vasconcelos, Nuno, Gopalacharyulu, Peddinti, Adrover, Anna, Jové Font, Mariona, Pamplona Gras, Reinald, Berenguer-Llergo, Antonio, Gordaliza, Isabel, Calvo, Enrique, Cabré, Noemí, Castro, Rui, Kuzmanic, Antonija, Boutant, Marie, Sala, David, Hyotylainen, Tuulia, Oresic, Matej, Fort, Joana, Errasti-Murugarren, Ekaitz, Orozco, Modesto, Joven, Jorge, Cantó, Carles, Palacin, Manuel, Fernández-Veledo, Sonia, Vendrell, Joan, Zorzano, Antonio
Tipo de recurso: artículo
Estado:Versión enviada para evaluación y publicación
Fecha de publicación:2019
País:España
Institución:Universitat de Lleida (UdL)
Repositorio:Repositori Obert UdL
OAI Identifier:oai:repositori.udl.cat:10459.1/70932
Acceso en línea:https://doi.org/10.1016/j.cell.2019.04.010
http://hdl.handle.net/10459.1/70932
Access Level:acceso abierto
Palabra clave:Mfn2
NASH
Phosphatidylserine
MAMs
Mitochondria
Phospholipid transfer
Descripción
Sumario: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.

Similares en LA Referencia