Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease

María Isabel Hernández-Alvarez (Corresponding Author), 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 & 13 others 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

Research output: Contribution to journalArticleScientificpeer-review

3 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

Fingerprint

Phosphatidylserines
Fatty Liver
Endoplasmic Reticulum
Liver
Liver Diseases
Mitochondrial Proteins
Liver Neoplasms
Mitochondria
Ablation
Endoplasmic Reticulum Stress
Lipid Metabolism
Phospholipids
Triglycerides
Fibrosis
Biopsy
Inflammation
Phenotype
Membranes
Neoplasms

Keywords

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

Cite this

Hernández-Alvarez, M. I., Sebastián, D., Vives, S., Ivanova, S., Bartoccioni, P., Kakimoto, P., ... 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
Hernández-Alvarez, María Isabel ; Sebastián, David ; Vives, Sara ; Ivanova, Saška ; Bartoccioni, Paola ; Kakimoto, Pamela ; Plana, Natalia ; Veiga, Sónia R. ; Hernández, Vanessa ; Vasconcelos, Nuno ; Peddinti, Gopal ; Adrover, Anna ; Jové, Mariona ; Pamplona, Reinald ; Gordaliza-Alaguero, Isabel ; Calvo, Enrique ; Cabré, Noemí ; Castro, Rui ; Kuzmanic, Antonija ; Boutant, Marie ; Sala, David ; Hyotylainen, Tuulia ; Orešič, Matej ; Fort, Joana ; Errasti-Murugarren, Ekaitz ; Rodrígues, Cecilia M.P. ; Orozco, Modesto ; Joven, Jorge ; Cantó, Carles ; Palacin, Manuel ; Fernández-Veledo, Sonia ; Vendrell, Joan ; Zorzano, Antonio. / Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease. In: Cell. 2019 ; Vol. 177, No. 4. pp. 881-895.e17.
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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 Saška 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 Orešič 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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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

Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease. / Hernández-Alvarez, María Isabel (Corresponding Author); Sebastián, David; Vives, Sara; Ivanova, Saška; Bartoccioni, Paola; Kakimoto, Pamela; Plana, Natalia; Veiga, Sónia R.; Hernández, Vanessa; Vasconcelos, Nuno; Peddinti, Gopal; Adrover, Anna; Jové, Mariona; Pamplona, Reinald; Gordaliza-Alaguero, Isabel; Calvo, Enrique; Cabré, Noemí; Castro, Rui; Kuzmanic, Antonija; Boutant, Marie; Sala, David; Hyotylainen, Tuulia; Orešič, Matej; Fort, Joana; Errasti-Murugarren, Ekaitz; Rodrígues, Cecilia M.P.; Orozco, Modesto; Joven, Jorge; Cantó, Carles; Palacin, Manuel; Fernández-Veledo, Sonia; Vendrell, Joan; Zorzano, Antonio (Corresponding Author).

In: Cell, Vol. 177, No. 4, 02.05.2019, p. 881-895.e17.

Research output: Contribution to journalArticleScientificpeer-review

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

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U2 - 10.1016/j.cell.2019.04.010

DO - 10.1016/j.cell.2019.04.010

M3 - Article

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SN - 0092-8674

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Hernández-Alvarez MI, Sebastián D, Vives S, Ivanova S, Bartoccioni P, Kakimoto P et al. Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease. Cell. 2019 May 2;177(4):881-895.e17. https://doi.org/10.1016/j.cell.2019.04.010