Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease

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 BoutantDavid 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*

*Corresponding author for this work

    Research output: Contribution to journalArticleScientificpeer-review

    283 Citations (Scopus)

    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. The mitochondrial protein mitofusin 2 binds and transfers phosphatidylserine across mitochondria-ER contacts, and perturbation of this process leads to aberrant lipid metabolism and liver diseases like NASH, NAFLD, and cancer.

    Original languageEnglish
    Pages (from-to)881-895.e17
    JournalCell
    Volume177
    Issue number4
    DOIs
    Publication statusPublished - 2 May 2019
    MoE publication typeA1 Journal article-refereed

    Funding

    M.I.H.-A. was recipient of a pre-doctoral fellowship from the CONACYT, Mexico and of a “Juan de la Cierva-Incorporación” fellowship from MICINN Spain. P.K. is recipient of a pre-doctoral fellowship from “Coordenação de Aperfeiçoamento do Pessoal de Nível Superior (CAPES).” M.J. is a Serra Húnter Fellow. This study was supported by the MINECO (SAF2016-75246R), the Generalitat de Catalunya (2014SGR48 , 2017SGR696 , ICREA Acadèmia), INFLAMES (PIE-14/00045 , ISCIII), CIBERDEM , ISCIII , INTERREG IV-B-SUDOE-FEDER (DIOMED, SOE1/P1/E178), and “la Caixa” Foundation. S.F.-V. acknowledges support from the Miguel Servet tenure-track program ( CP10/00438 and CPII16/00008 ) from the Fondo de Investigación Sanitaria , co-financed by the ERD. We gratefully acknowledge institutional funding from the MINECO through the Centres of Excellence Severo Ochoa Award and from the CERCA Programme of the Generalitat de Catalunya .

    Keywords

    • MAMs
    • Mfn2
    • mitochondria
    • NASH
    • phosphatidylserine
    • phospholipid transfer

    Fingerprint

    Dive into the research topics of 'Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease'. Together they form a unique fingerprint.

    Cite this