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Cell. 2019 May 2;177(4):881-895.e17. doi: 10.1016/j.cell.2019.04.010.

Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease.

Author information

1
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain. Electronic address: misabel.hernandez.alvarez@gmail.com.
2
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
3
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
4
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; CIBERER, Instituto de Salud Carlos III, Madrid, Spain.
5
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departamento de Bioquímica, Instituto de Química, Universidad de São Paulo, São Paulo, Brazil.
6
Laboratory of Metabolism and Cancer, Catalan Institute of Oncology, ICO, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
7
VTT Technical Research Center of Finland, Espoo, Finland.
8
Department of Experimental Medicine, University of Lleida-Lleida Biomedical Research Institute (UdL-IRBLleida), Lleida, Spain.
9
Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain.
10
Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; Universitat Rovira i Virgili, Department of Medicine and Surgery, Reus, Spain; Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Reus, Spain.
11
Research Institute for Medicines (iMed.ULisboa), and Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal.
12
Nestlé Institute of Health Sciences SA, Lausanne, Switzerland.
13
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
14
Department of Chemistry, University of Örebro, Örebro, Sweden.
15
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
16
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBERER, Instituto de Salud Carlos III, Madrid, Spain.
17
Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain.
18
Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain; Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain; Universitat Rovira i Virgili, Tarragona, Spain.
19
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biología, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: antonio.zorzano@irbbarcelona.org.

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.

KEYWORDS:

MAMs; Mfn2; NASH; mitochondria; phosphatidylserine; phospholipid transfer

PMID:
31051106
DOI:
10.1016/j.cell.2019.04.010

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