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 | |
| Publication status | Published - 2 May 2019 |
| MoE publication type | A1 Journal article-refereed |
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Keywords
- MAMs
- Mfn2
- mitochondria
- NASH
- phosphatidylserine
- phospholipid transfer
Cite this
}
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 journal › Article › Scientific › peer-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
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
VL - 177
SP - 881-895.e17
JO - Cell
JF - Cell
SN - 0092-8674
IS - 4
ER -