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

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...

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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:	Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:	Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:	oai:recercat.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

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spelling	Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver diseaseHernández-Alvarez, María IsabelSebastián, DavidVives, SaraIvanova, Sa kaBartoccioni, PaolaKakimoto, PamelaPlana, NataliaVeiga, Sónia R.Hernández, VanessaVasconcelos, NunoGopalacharyulu, PeddintiAdrover, AnnaJové Font, MarionaPamplona Gras, ReinaldBerenguer-Llergo, AntonioGordaliza, IsabelCalvo, EnriqueCabré, NoemíCastro, RuiKuzmanic, AntonijaBoutant, MarieSala, DavidHyotylainen, TuuliaOresic, MatejFort, JoanaErrasti-Murugarren, EkaitzOrozco, ModestoJoven, JorgeCantó, CarlesPalacin, ManuelFernández-Veledo, SoniaVendrell, JoanZorzano, AntonioMfn2NASHPhosphatidylserineMAMsMitochondriaPhospholipid transferNon-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.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.Elsevier2021202120192021info:eu-repo/semantics/articleinfo:eu-repo/semantics/submittedVersionapplication/pdfhttps://doi.org/10.1016/j.cell.2019.04.010http://hdl.handle.net/10459.1/70932http://hdl.handle.net/10459.1/70932reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)Inglésinfo:eu-repo/grantAgreement/MINECO//SAF2016-75246-RVersió preprint del document publicat a: https://doi.org/10.1016/j.cell.2019.04.010Cell, 2019, vol. 177, núm. 4, p. 881-895(c) Elsevier, 2019info:eu-repo/semantics/openAccessoai:recercat.cat:10459.1/709322026-05-29T05:05:01Z
dc.title.none.fl_str_mv	Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver disease
title	Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver disease
spellingShingle	Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver disease Hernández-Alvarez, María Isabel Mfn2 NASH Phosphatidylserine MAMs Mitochondria Phospholipid transfer
title_short	Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver disease
title_full	Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver disease
title_fullStr	Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver disease
title_full_unstemmed	Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver disease
title_sort	Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver disease
dc.creator.none.fl_str_mv	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
author	Hernández-Alvarez, María Isabel
author_facet	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
author_role	author
author2	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
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	Mfn2 NASH Phosphatidylserine MAMs Mitochondria Phospholipid transfer
topic	Mfn2 NASH Phosphatidylserine MAMs Mitochondria Phospholipid transfer
description	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.
publishDate	2019
dc.date.none.fl_str_mv	2019 2021 2021 2021
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/submittedVersion
format	article
status_str	submittedVersion
dc.identifier.none.fl_str_mv	https://doi.org/10.1016/j.cell.2019.04.010 http://hdl.handle.net/10459.1/70932 http://hdl.handle.net/10459.1/70932
url	https://doi.org/10.1016/j.cell.2019.04.010 http://hdl.handle.net/10459.1/70932
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	info:eu-repo/grantAgreement/MINECO//SAF2016-75246-R Versió preprint del document publicat a: https://doi.org/10.1016/j.cell.2019.04.010 Cell, 2019, vol. 177, núm. 4, p. 881-895
dc.rights.none.fl_str_mv	(c) Elsevier, 2019 info:eu-repo/semantics/openAccess
rights_invalid_str_mv	(c) Elsevier, 2019
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	Elsevier
publisher.none.fl_str_mv	Elsevier
dc.source.none.fl_str_mv	reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str	Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str	Recercat. Dipósit de la Recerca de Catalunya
collection	Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver disease

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