Deficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver disease

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dc.contributor.authorHernández-Alvarez, María Isabel
dc.contributor.authorSebastián, David
dc.contributor.authorVives, Sara
dc.contributor.authorIvanova, Sa ka
dc.contributor.authorBartoccioni, Paola
dc.contributor.authorKakimoto, Pamela
dc.contributor.authorPlana, Natalia
dc.contributor.authorVeiga, Sónia R.
dc.contributor.authorHernández, Vanessa
dc.contributor.authorVasconcelos, Nuno
dc.contributor.authorGopalacharyulu, Peddinti
dc.contributor.authorAdrover, Anna
dc.contributor.authorJové Font, Mariona
dc.contributor.authorPamplona Gras, Reinald
dc.contributor.authorBerenguer-Llergo, Antonio
dc.contributor.authorGordaliza, Isabel
dc.contributor.authorCalvo, Enrique
dc.contributor.authorCabré, Noemí
dc.contributor.authorCastro, Rui
dc.contributor.authorKuzmanic, Antonija
dc.contributor.authorBoutant, Marie
dc.contributor.authorSala, David
dc.contributor.authorHyotylainen, Tuulia
dc.contributor.authorOresic, Matej
dc.contributor.authorFort, Joana
dc.contributor.authorErrasti-Murugarren, Ekaitz
dc.contributor.authorOrozco, Modesto
dc.contributor.authorJoven, Jorge
dc.contributor.authorCantó, Carles
dc.contributor.authorPalacin, Manuel
dc.contributor.authorFernández-Veledo, Sonia
dc.contributor.authorVendrell, Joan
dc.contributor.authorZorzano, Antonio
dc.date.accessioned2021-04-07T08:44:04Z
dc.date.available2021-04-07T08:44:04Z
dc.date.issued2019-05-02
dc.date.updated2021-04-07T08:44:04Z
dc.description.abstractNon-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.
dc.description.sponsorshipThis 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.
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1016/j.cell.2019.04.010
dc.identifier.idgrec029375
dc.identifier.issn0092-8674
dc.identifier.urihttp://hdl.handle.net/10459.1/70932
dc.language.isoeng
dc.publisherElsevier
dc.relationinfo:eu-repo/grantAgreement/MINECO//SAF2016-75246-R/ES/
dc.relation.isformatofVersió preprint del document publicat a: https://doi.org/10.1016/j.cell.2019.04.010
dc.relation.ispartofCell, 2019, vol. 177, núm. 4, p. 881-895
dc.rights(c) Elsevier, 2019
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.subjectMfn2
dc.subjectNASH
dc.subjectPhosphatidylserine
dc.subjectMAMs
dc.subjectMitochondria
dc.subjectPhospholipid transfer
dc.titleDeficient endoplasmic reticulum-mitochondrial phosphatidylserine transfer causes liver disease
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/submittedVersion
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