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
N1 - Funding Information:
We thank Jennifer Rieusset for the BIP adenovirus, Estela Area-Gomez for the protocol of phospholipid synthesis, Helena Cortez-Pinto (Hospital Santa María, Lisbon) for liver biopsies, Mar García-Rocha for discussion, Jorge Manuel Seco and Laura Alcaide for technological assistance, Neus Prats and the Histopathology Core Facility (IRB Barcelona), and Raquel Garcia-Castellanos and the Protein Expression Core Facility (IRB Barcelona) for cloning and production of Mfn2 and Mfn1 constructs in E. coli. We also thank the Mouse Mutant, Mass Spectrometry & Proteomics, Advanced Digital Microscopy (ADM), and the Biostatistics/Bioinformatics Core Facilities (IRB Barcelona); the Lipidomics Unit of IRB Lleida; the Unit of Electron Cryo-Microscopy (UB); and Iris Joval for the artwork. 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 .
Funding Information:
We thank Jennifer Rieusset for the BIP adenovirus, Estela Area-Gomez for the protocol of phospholipid synthesis, Helena Cortez-Pinto (Hospital Santa María, Lisbon) for liver biopsies, Mar García-Rocha for discussion, Jorge Manuel Seco and Laura Alcaide for technological assistance, Neus Prats and the Histopathology Core Facility (IRB Barcelona), and Raquel Garcia-Castellanos and the Protein Expression Core Facility (IRB Barcelona) for cloning and production of Mfn2 and Mfn1 constructs in E. coli. We also thank the Mouse Mutant, Mass Spectrometry & Proteomics, Advanced Digital Microscopy (ADM), and the Biostatistics/Bioinformatics Core Facilities (IRB Barcelona); the Lipidomics Unit of IRB Lleida; the Unit of Electron Cryo-Microscopy (UB); and Iris Joval for the artwork. 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. M.I.H.-A. conceived, designed the study and the strategy, performed experiments, discussed the results, and wrote the manuscript. D. Sebastián, S.V. P.B. P.K. N.P. S.R.V. V.H. N.V. G.P. A.A. M.J. R.P. I.G.-A. E.C. N.C. R.C. A.K. M.B. D. Sala, T.H. J.F. E.E.-M. and C.M.P.R. performed experiments. S.I. conceived and performed experiments. J.J. M. Oresic, M. Orozco, C.C. M.P. S.F.-V. and J.V. revised experimental data and contributed to the discussion. A.Z. designed the study and the strategy, discussed the results, and wrote the manuscript. The authors declare no conflict of interest. C.C. and M.B. are employees of the Nestlé Institute of Health Sciences S.A.
Publisher Copyright:
© 2019
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 -
