Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver disease

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

doi:https://doi.org/10.1016/j.cell.2019.04.010

Visualitza/Obre

Preprint (7.551Mb)

Data de publicació

2019-05-02

Autor/a

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

Citació recomanada

Hernández-Alvarez, María Isabel; Sebastián, David; Vives, Sara; Ivanova, Sa ka; Bartoccioni, Paola; Kakimoto, Pamela; ... Zorzano, Antonio. (2019) . Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver disease. Cell, 2019, vol. 177, núm. 4, p. 881-895. https://doi.org/10.1016/j.cell.2019.04.010.

Resum

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.

URI

http://hdl.handle.net/10459.1/70932

DOI

https://doi.org/10.1016/j.cell.2019.04.010

És part de

Cell, 2019, vol. 177, núm. 4, p. 881-895

Col·leccions

Publicacions de projectes de recerca del Plan Nacional [2268]
Articles publicats (IRBLleida) [863]
Articles publicats (Medicina Experimental) [259]

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