Boosting mitochondria activity by silencing MCJ overcomes cholestasis-induced liver injury.

ALP, alkaline phosphatase ALT, alanine aminotransferase AMA-M2, antimitochondrial M2 antibody ANA, antinuclear antibodies APRI, AST to platelet ratio index AST, aspartate aminotransferase Abs, antibodies BA, bile acid BAX, BCL2 associated X BCL-2, B-cell lymphoma 2 BCL-Xl, B-cell lymphoma-extra large BDL, bile duct ligation Bile duct ligation CLD, cholestatic liver disease Ccl2, C-C motif chemokine ligand 2 Ccr2, C-C motif chemokine receptor 2 Ccr5, C-C motif chemokine receptor 5 Cholestasis Cxcl1, C-X-C motif chemokine ligand 1 Cyp7α1, cholesterol 7 alpha-hydroxylase DCA, deoxycholic acid ETC, electron transport chain Ezh2, enhancer of zeste homolog 2 Fxr, farnesoid X receptor GAPDH, glyceraldehyde-3-phosphate dehydrogenase GCDCA, glycochenodeoxycholic acid HSC, hepatic stellate cells Hif-1α, hypoxia-inducible factor 1-alpha JNK, c-Jun N-terminal kinase KO, knockout LSM, liver stiffness MAPK, mitogen-activated protein kinase MCJ MCJ, methylation-controlled J MLKL, mixed-lineage kinase domain-like pseudokinase MMP, mitochondrial membrane potential MPO, myeloperoxidase MPT, mitochondrial permeability transition Mitochondria Nrf1, nuclear respiratory factor 1 PARP, poly (ADP-ribose) polymerase PBC, primary biliary cholangitis PSC, primary sclerosing cholangitis Pgc1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha Pgc1β, peroxisome proliferator-activated receptor gamma coactivator 1-beta ROS ROS, reactive oxygen species RT, room temperature SDH2, succinate dehydrogenase TNF, tumour necrosis factor Tfam, transcription factor A mitochondrial Trail, TNF-related apoptosis-inducing ligand UDCA, ursodeoxycholic acid Ucp2, uncoupling protein 2 VCTE, vibration-controlled transient elastography WT, wild-type mRNA, messenger ribonucleic acid p-JNK, phosphor-JNK p-MLKL, phosphor-MLKL shRNA, small hairpin RNA siRNA, small interfering RNA tBIL, total bilirubin α-SMA, alpha-smooth muscle actin

Journal

JHEP reports : innovation in hepatology
ISSN: 2589-5559
Titre abrégé: JHEP Rep
Pays: Netherlands
ID NLM: 101761237

Informations de publication

Date de publication:
Jun 2021
Historique:
received: 14 05 2020
revised: 24 02 2021
accepted: 27 02 2021
entrez: 17 5 2021
pubmed: 18 5 2021
medline: 18 5 2021
Statut: epublish

Résumé

Mitochondria are the major organelles for the formation of reactive oxygen species (ROS) in the cell, and mitochondrial dysfunction has been described as a key factor in the pathogenesis of cholestatic liver disease. The methylation-controlled J-protein (MCJ) is a mitochondrial protein that interacts with and represses the function of complex I of the electron transport chain. The relevance of MCJ in the pathology of cholestasis has not yet been explored. We studied the relationship between MCJ and cholestasis-induced liver injury in liver biopsies from patients with chronic cholestatic liver diseases, and in livers and primary hepatocytes obtained from WT and MCJ-KO mice. Bile duct ligation (BDL) was used as an animal model of cholestasis, and primary hepatocytes were treated with toxic doses of bile acids. We evaluated the effect of MCJ silencing for the treatment of cholestasis-induced liver injury. Elevated levels of MCJ were detected in the liver tissue of patients with chronic cholestatic liver disease when compared with normal liver tissue. Likewise, in mouse models, the hepatic levels of MCJ were increased. After BDL, MCJ-KO animals showed significantly decreased inflammation and apoptosis. In an We demonstrated that MCJ is involved in the progression of cholestatic liver injury, and our results identified MCJ as a potential therapeutic target to mitigate the liver injury caused by cholestasis. In this study, we examine the effect of mitochondrial respiratory chain inhibition by MCJ on bile acid-induced liver toxicity. The loss of MCJ protects hepatocytes against apoptosis, mitochondrial ROS overproduction, and ATP depletion as a result of bile acid toxicity. Our results identify MCJ as a potential therapeutic target to mitigate liver injury in cholestatic liver diseases.

Sections du résumé

BACKGROUND & AIMS OBJECTIVE
Mitochondria are the major organelles for the formation of reactive oxygen species (ROS) in the cell, and mitochondrial dysfunction has been described as a key factor in the pathogenesis of cholestatic liver disease. The methylation-controlled J-protein (MCJ) is a mitochondrial protein that interacts with and represses the function of complex I of the electron transport chain. The relevance of MCJ in the pathology of cholestasis has not yet been explored.
METHODS METHODS
We studied the relationship between MCJ and cholestasis-induced liver injury in liver biopsies from patients with chronic cholestatic liver diseases, and in livers and primary hepatocytes obtained from WT and MCJ-KO mice. Bile duct ligation (BDL) was used as an animal model of cholestasis, and primary hepatocytes were treated with toxic doses of bile acids. We evaluated the effect of MCJ silencing for the treatment of cholestasis-induced liver injury.
RESULTS RESULTS
Elevated levels of MCJ were detected in the liver tissue of patients with chronic cholestatic liver disease when compared with normal liver tissue. Likewise, in mouse models, the hepatic levels of MCJ were increased. After BDL, MCJ-KO animals showed significantly decreased inflammation and apoptosis. In an
CONCLUSIONS CONCLUSIONS
We demonstrated that MCJ is involved in the progression of cholestatic liver injury, and our results identified MCJ as a potential therapeutic target to mitigate the liver injury caused by cholestasis.
LAY SUMMARY BACKGROUND
In this study, we examine the effect of mitochondrial respiratory chain inhibition by MCJ on bile acid-induced liver toxicity. The loss of MCJ protects hepatocytes against apoptosis, mitochondrial ROS overproduction, and ATP depletion as a result of bile acid toxicity. Our results identify MCJ as a potential therapeutic target to mitigate liver injury in cholestatic liver diseases.

Identifiants

DOI: 10.1016/j.jhepr.2021.100276 PMID: 33997750 PMC: PMC8099785
pubmed: 33997750
doi: 10.1016/j.jhepr.2021.100276
pii: S2589-5559(21)00052-5
pmc: PMC8099785
doi:

Types de publication

Journal Article

Langues

eng

Pagination

100276

Informations de copyright

© 2021 The Author(s).

Déclaration de conflit d'intérêts

Dr. María Luz Martínez-Chantar advises for Mitotherapeutix LLC. Dr. Javier Crespo reports grants and research support from Gilead Sciences, AbbVie, MSD, and Intercept Pharmaceuticals (all outside the scope of the submitted work). He is a speaker for Gilead Sciences and AbbVie. Please refer to the accompanying ICMJE disclosure forms for further details.

Références

Cell Death Dis. 2016 Sep 29;7(9):e2390
pubmed: 27685634
Hepatology. 1994 Feb;19(2):471-9
pubmed: 7904981
Am J Physiol Gastrointest Liver Physiol. 2011 Jul;301(1):G119-27
pubmed: 21415417
Gastroenterology. 2000 Jun;118(6):1157-68
pubmed: 10833491
J Hepatol. 2017 Jul;67(1):145-172
pubmed: 28427765
J Vis Exp. 2015 Feb 10;(96):
pubmed: 25741630
J Infect Dis. 2015 Jan 1;211(1):135-45
pubmed: 25028693
Nat Commun. 2017 Dec 12;8(1):2068
pubmed: 29233977
J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Dec 1;860(1):10-7
pubmed: 17997366
Hepatology. 1999 Feb;29(2):443-50
pubmed: 9918921
Gastroenterology. 2007 Jun;132(7):2504-17
pubmed: 17570222
Adv Exp Med Biol. 2012;942:3-37
pubmed: 22399416
Curr Drug Targets. 2017;18(8):921-931
pubmed: 26477457
J Med Genet. 2011 Apr;48(4):219-25
pubmed: 21278388
Hepatology. 2018 May;67(5):2013-2024
pubmed: 29194686
Nature. 2016 Sep 29;537(7622):644-648
pubmed: 27654913
Hepatology. 2017 Feb;65(2):694-709
pubmed: 28035772
N Engl J Med. 2016 Aug 18;375(7):631-43
pubmed: 27532829
Nat Commun. 2020 Jul 3;11(1):3360
pubmed: 32620763
Hepatology. 2009 Jul;50(1):291-308
pubmed: 19554543
Hepatology. 2006 Feb;43(2 Suppl 1):S31-44
pubmed: 16447272
Biosci Rep. 2001 Feb;21(1):73-80
pubmed: 11508696
Free Radic Biol Med. 2013 Aug;61:218-28
pubmed: 23597504
J Hepatol. 2002 Nov;37(5):601-5
pubmed: 12399225
Liver Int. 2012 Jan;32(1):58-69
pubmed: 22098667
Br J Surg. 2008 May;95(5):646-56
pubmed: 18196571
Toxicol Sci. 2000 Sep;57(1):177-85
pubmed: 10966524
Cell Death Differ. 2019 Jan;26(1):41-52
pubmed: 30341422
N Engl J Med. 1998 Oct 22;339(17):1217-27
pubmed: 9780343
Free Radic Biol Med. 2016 Aug;97:466-477
pubmed: 27387768
Immunity. 2016 Jun 21;44(6):1299-311
pubmed: 27234056
Hepatology. 2017 Feb;65(2):722-738
pubmed: 27981592
Biochim Biophys Acta. 2003 Mar 20;1637(2):142-50
pubmed: 12633902
Nat Rev Genet. 2015 Sep;16(9):543-52
pubmed: 26281785
Front Biosci (Elite Ed). 2012 Jan 01;4(6):2233-52
pubmed: 22202034
Pharmacol Ther. 1993 Oct;60(1):1-38
pubmed: 8127921
Med Hypotheses. 1986 Jan;19(1):57-69
pubmed: 2871479
Hepatology. 2003 Aug;38(2):355-63
pubmed: 12883479
Mol Cell Biol. 2013 Jun;33(11):2302-14
pubmed: 23530063
Mitochondrion. 2003 Mar;2(4):305-11
pubmed: 16120330
Hepatology. 1998 Nov;28(5):1260-8
pubmed: 9794910
Antioxid Redox Signal. 2013 Jun 1;18(16):2029-74
pubmed: 23244576
Gastroenterology. 2006 Jul;131(1):223-32
pubmed: 16831604
Apoptosis. 2009 Jul;14(7):890-9
pubmed: 19462240
Gastroenterology. 2018 Sep;155(3):629-647
pubmed: 30012333
Mol Cell Biol. 2007 Apr;27(8):2952-66
pubmed: 17283040

Auteurs

Paula Iruzubieta (P)

Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, Clinical and Translational Digestive Research Group, IDIVAL, Santander, Spain.

Naroa Goikoetxea-Usandizaga (N)

Liver Disease and Liver Metabolism Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain.

Lucía Barbier-Torres (L)

Liver Disease and Liver Metabolism Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain.

Marina Serrano-Maciá (M)

Liver Disease and Liver Metabolism Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain.

David Fernández-Ramos (D)

Liver Disease and Liver Metabolism Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain.

Pablo Fernández-Tussy (P)

Liver Disease and Liver Metabolism Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain.

Virginia Gutiérrez-de-Juan (V)

Liver Disease and Liver Metabolism Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain.

Sofia Lachiondo-Ortega (S)

Liver Disease and Liver Metabolism Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain.

Jorge Simon (J)

Liver Disease and Liver Metabolism Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain.

Miren Bravo (M)

Liver Disease and Liver Metabolism Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain.

Fernando Lopitz-Otsoa (F)

Liver Disease and Liver Metabolism Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain.

Mercedes Robles (M)

Liver Unit, Vírgen de Victoria University Hospital, Gastroenterology Service and Department of Medicine, University of Málaga, Malaga, Spain.

Carlos Ferre-Aracil (C)

Liver Unit, Puerta de Hierro University Hospital, IDIPHISA, CIBERehd, Madrid, Spain.

Marta Varela-Rey (M)

Liver Disease and Liver Metabolism Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain.

Natalia Elguezabal (N)

Departmento de Sanidad Animal, NEIKER-Instituto Vasco de Investigación y Desarrollo Agrario, Derio, Spain.

José Luis Calleja (JL)

Liver Unit, Puerta de Hierro University Hospital, IDIPHISA, CIBERehd, Madrid, Spain.

Shelly C Lu (SC)

Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Malgorzata Milkiewicz (M)

Department of Medical Biology, Pomeranian Medical University, Szczecin, Poland.

Piotr Milkiewicz (P)

Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland.

Juan Anguita (J)

Inflammation and Macrophage Plasticity Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Derio, Spain.
Ikerbasque, Basque Foundation for Science, Bilbao, Spain.

María J Monte (MJ)

Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain.

José J G Marin (JJG)

Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain.

Marcos López-Hoyos (M)

Immunology Department, University Hospital Marqués de Valdecilla, IDIVAL, Santander, Spain.

Teresa C Delgado (TC)

Liver Disease and Liver Metabolism Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain.

Mercedes Rincón (M)

Department of Medicine, University of Vermont College of Medicine, Burlington, VT, USA.

Javier Crespo (J)

Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital, Clinical and Translational Digestive Research Group, IDIVAL, Santander, Spain.

María Luz Martínez-Chantar (ML)

Liver Disease and Liver Metabolism Laboratory, CIC bioGUNE-BRTA (Basque Research & Technology Alliance), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain.

Classifications MeSH