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 Boutant; David 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

doi:10.1016/j.cell.2019.04.010

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 journal › Article › Scientific › peer-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 language	English
Pages (from-to)	881-895.e17
Journal	Cell
Volume	177
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2019.04.010
Publication status	Published - 2 May 2019
MoE publication type	A1 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2019.04.010

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Hernández-Alvarez, M. I., Sebastián, D., Vives, S., Ivanova, S., Bartoccioni, P., Kakimoto, P., Plana, N., Veiga, S. R., Hernández, V., Vasconcelos, N., Peddinti, G., Adrover, A., Jové, M., Pamplona, R., Gordaliza-Alaguero, I., Calvo, E., Cabré, N., Castro, R., Kuzmanic, A., ... Zorzano, A. (2019). Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease. Cell, 177(4), 881-895.e17. https://doi.org/10.1016/j.cell.2019.04.010

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title = "Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease",

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.",

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author = "Hern{\'a}ndez-Alvarez, {Mar{\'i}a Isabel} and David Sebasti{\'a}n and Sara Vives and Sa{\v s}ka Ivanova and Paola Bartoccioni and Pamela Kakimoto and Natalia Plana and Veiga, {S{\'o}nia R.} and Vanessa Hern{\'a}ndez and Nuno Vasconcelos and Gopal Peddinti and Anna Adrover and Mariona Jov{\'e} and Reinald Pamplona and Isabel Gordaliza-Alaguero and Enrique Calvo and Noem{\'i} Cabr{\'e} and Rui Castro and Antonija Kuzmanic and Marie Boutant and David Sala and Tuulia Hyotylainen and Matej Ore{\v s}i{\v c} and Joana Fort and Ekaitz Errasti-Murugarren and Rodr{\'i}gues, {Cecilia M.P.} and Modesto Orozco and Jorge Joven and Carles Cant{\'o} and Manuel Palacin and Sonia Fern{\'a}ndez-Veledo and Joan Vendrell and Antonio Zorzano",

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doi = "10.1016/j.cell.2019.04.010",

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Hernández-Alvarez, MI, Sebastián, D, Vives, S, Ivanova, S, Bartoccioni, P, Kakimoto, P, Plana, N, Veiga, SR, Hernández, V, Vasconcelos, N, Peddinti, G, Adrover, A, Jové, M, Pamplona, R, Gordaliza-Alaguero, I, Calvo, E, Cabré, N, Castro, R, Kuzmanic, A, Boutant, M, Sala, D, Hyotylainen, T, Orešič, M, Fort, J, Errasti-Murugarren, E, Rodrígues, CMP, Orozco, M, Joven, J, Cantó, C, Palacin, M, Fernández-Veledo, S, Vendrell, J & Zorzano, A 2019, 'Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease', Cell, vol. 177, no. 4, pp. 881-895.e17. https://doi.org/10.1016/j.cell.2019.04.010

TY - JOUR

T1 - Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease

AU - Hernández-Alvarez, María Isabel

AU - Sebastián, David

AU - Vives, Sara

AU - Ivanova, Saška

AU - Bartoccioni, Paola

AU - Kakimoto, Pamela

AU - Plana, Natalia

AU - Veiga, Sónia R.

AU - Hernández, Vanessa

AU - Vasconcelos, Nuno

AU - Peddinti, Gopal

AU - Adrover, Anna

AU - Jové, Mariona

AU - Pamplona, Reinald

AU - Gordaliza-Alaguero, Isabel

AU - Calvo, Enrique

AU - Cabré, Noemí

AU - Castro, Rui

AU - Kuzmanic, Antonija

AU - Boutant, Marie

AU - Sala, David

AU - Hyotylainen, Tuulia

AU - Orešič, Matej

AU - Fort, Joana

AU - Errasti-Murugarren, Ekaitz

AU - Rodrígues, Cecilia M.P.

AU - Orozco, Modesto

AU - Joven, Jorge

AU - Cantó, Carles

AU - Palacin, Manuel

AU - Fernández-Veledo, Sonia

AU - Vendrell, Joan

AU - Zorzano, Antonio

PY - 2019/5/2

Y1 - 2019/5/2

N2 - 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.

AB - 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.

KW - MAMs

KW - Mfn2

KW - mitochondria

KW - NASH

KW - phosphatidylserine

KW - phospholipid transfer

UR - http://www.scopus.com/inward/record.url?scp=85064698279&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2019.04.010

DO - 10.1016/j.cell.2019.04.010

M3 - Article

AN - SCOPUS:85064698279

SN - 0092-8674

VL - 177

SP - 881-895.e17

JO - Cell

JF - Cell

IS - 4

ER -

Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease

Abstract

Funding

Keywords

UN SDGs

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