ArticleNature communications2017
The mitochondrial negative regulator MCJ is a therapeutic target for acetaminophen-induced liver injury.
Open access · goldAbstract readComparative Study
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Article in Nature communications, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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59citing papers in PubMed
7.7field-weighted citation impact, top 2% of its field
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59 citing papers in PubMed, 110 citations in OpenAlex.
- Combined metabolic activators therapy ameliorates liver fat in nonalcoholic fatty liver disease patients.Molecular systems biology · 2021Trial
- Membrane-Targeted Consequences of Acetaminophen Toxicity and Off-Target Effects of Antimicrobial Peptides on Host Cell Membranes.International journal of molecular sciences · 2026Review
- Flavescensines A-L: Novel azaspiro[4.4] heterodimeric alkaloids fromActa pharmaceutica Sinica. B · 2026Article
- Targeting magnesium homeostasis: a novel therapeutic strategy for liver diseases.Frontiers in nutrition · 2026Review
- Biomimetic polymersomal nanoreactors for hepatocyte-directed detoxification in drug-induced liver injury.Materials today. Bio · 2025Article
- Genomic medicine in hepatology: mechanisms and liver treatment strategies.Molecular medicine (Cambridge, Mass.) · 2025Review
- Mitochondrial Dysfunction: Unraveling the Elusive Biology Behind Anti-TNF Response During Ulcerative Colitis.Inflammatory bowel diseases · 2025Article
- S-adenosylmethionine deficit disrupts very low-density lipoprotein metabolism promoting liver lipid accumulation in mice.Journal of lipid research · 2025Article
- HIF2α drives ccRCC metastasis through transcriptional activation of methylation-controlled J protein and enhanced prolegumain secretion.Cell death & disease · 2025Article
- Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics.Signal transduction and targeted therapy · 2025Review
- Burn-induced mitochondrial dysfunction in hepatocytes: The role of methylation-controlled J protein silencing.The journal of trauma and acute care surgery · 2025Article
- Nanotuner targeting mitochondrial redox and iron homeostasis imbalance for the treatment of acute liver injury.Theranostics · 2025Article
- Akkermansia muciniphila Mediated the Preventive Effect of Disulfiram on Acute Liver Injury via PI3K/Akt Pathway.Microbial biotechnology · 2025Article
- Investigating impacts of the mycothiazole chemotype as a chemical probe for the study of mitochondrial function and aging.GeroScience · 2024Article
- Sirtuin 5-Mediated Desuccinylation of ALDH2 Alleviates Mitochondrial Oxidative Stress Following Acetaminophen-Induced Acute Liver Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway.Cell reports. Medicine · 2024Article
- Oligonucleotide therapies for nonalcoholic steatohepatitis.Molecular therapy. Nucleic acids · 2024Review
- Bifidobacterium adolescentis-derived hypaphorine alleviates acetaminophen hepatotoxicity by promoting hepatic Cry1 expression.Journal of translational medicine · 2024Article
- Deleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8Nature communications · 2024Article
- Acetaminophen overdose-induced acute liver injury can be alleviated by static magnetic field.Zoological research · 2024Article
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Authors and funding
29 authors at 11 institutions in 4 countries.
Lucía Barbier-TorresLiver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain.
Paula IruzubietaLiver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain.
David Fernández-RamosLiver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain.
Teresa C DelgadoLiver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain.
Daniel TaiboLiver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain.
Virginia Guitiérrez-de-JuanLiver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain.
Marta Varela-ReyLiver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain.
Mikel AzkargortaProteomics Platform, CIC bioGUNE, CIBERehd, ProteoRed-ISCIII, Bizkaia Science and Technology Park, Derio, 48160, Spain.
Nicolas NavasaMacrophage and Tick Vaccine Laboratory, CIC bioGUNE, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain.
Pablo Fernández-TussyLiver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain.
Imanol Zubiete-FrancoLiver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain.
Jorge SimonLiver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain.
Fernando Lopitz-OtsoaLiver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain.
Sofia Lachiondo-OrtegaLiver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain.
Javier CrespoDepartment of Gastroenterology and Hepatology, Marqués de Valdecilla University Hospital, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). Infection, Immunity and Digestive Pathology Group, Research Institute Marqués de Valdecilla (IDIVAL), Santander, 39008, Spain.
Steven MassonThe Liver Unit, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE2 7DN, UK.
Misti Vanette McCainNorthern Institute of Cancer Research, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 7DN, UK.
Erica VillaGastroenterology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, Modena, 41124, Italy.ORCID http://orcid.org/0000-0001-6388-7022
Helen ReevesThe Liver Unit, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE2 7DN, UK.
Felix ElortzaProteomics Platform, CIC bioGUNE, CIBERehd, ProteoRed-ISCIII, Bizkaia Science and Technology Park, Derio, 48160, Spain.
Maria Isabel LucenaUniversity Hospital Virgen de la Victoria, Málaga, 29010, Spain.ORCID http://orcid.org/0000-0001-9586-4896
Maria Isabel Hernández-AlvarezInstitute for Research in Biomedicine (IRB Barcelona), Barcelona, 08028, Spain.ORCID http://orcid.org/0000-0001-9586-4896
Antonio ZorzanoInstitute for Research in Biomedicine (IRB Barcelona), Barcelona, 08028, Spain.
Raúl J AndradeUniversity Hospital Virgen de la Victoria, Málaga, 29010, Spain.
Shelly C LuDivision of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, 90048, CA, USA.
José M MatoLiver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain.
Juan AnguitaMacrophage and Tick Vaccine Laboratory, CIC bioGUNE, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain.ORCID http://orcid.org/0000-0003-2061-7182
Mercedes RincónDepartment of Medicine, University of Vermont College of Medicine, Burlington, 05405, VT, USA. mercedes.rincon@uvm.edu.
María Luz Martínez-ChantarLiver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain. mlmartinez@cicbiogune.es.
Euskadiko Parke Teknologikoa · ESCentro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas · ESHospital Clínico Universitario Virgen de la Victoria · ESInstitute of Cancer Research · GBInstituto de Salud Carlos III · ESCedars-Sinai Medical Center · USIkerbasque · ESMarqués de Valdecilla University Hospital · ESNewcastle upon Tyne Hospitals NHS Foundation Trust · GBUniversity of Modena and Reggio Emilia · ITUniversity of Vermont · US
Funding
Role of SAMe in Pathogenesis and Treatment of Non-Alcholic Fatty Liver DiseaseR01AT001576 · NCCIH · UNIVERSITY OF SOUTHERN CALIFORNIA · PI LU, SHELLY CHI-LOO · 2002 to 2018
$5.0MPROHIBITIN 1 IN LIVER INJURY AND CANCERR01CA172086 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI LU, SHELLY CHI-LOO · 2014 to 2018
$1.6MMCJ function in mouse mammary tumor propertiesR21CA127099 · NCI · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · PI RINCON, MERCEDES · 2008 to 2009
$438kMetabolic Regulation of Caspases and Survival in T CellsR21AI119979 · NIAID · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · PI BUDD, RALPH C · 2016 to 2017
$426kA Novel Treatment for Acetominophen-Induced Liver InjuryR41DK117760 · NIDDK · MITOTHERAPEUTIX, LLC · PI RINCON, MERCEDES · 2018 to 2018
$264kNCCIH NIH HHS R01 AT001576NCI NIH HHS R01 CA172086NCI NIH HHS R21 CA127099NIAID NIH HHS R21 AI119979NIDDK NIH HHS R41 DK117760
Abstract
Acetaminophen (APAP) is the active component of many medications used to treat pain and fever worldwide. Its overuse provokes liver injury and it is the second most common cause of liver failure. Mitochondrial dysfunction contributes to APAP-induced liver injury but the mechanism by which APAP causes hepatocyte toxicity is not completely understood. Therefore, we lack efficient therapeutic strategies to treat this pathology. Here we show that APAP interferes with the formation of mitochondrial respiratory supercomplexes via the mitochondrial negative regulator MCJ, and leads to decreased production of ATP and increased generation of ROS. In vivo treatment with an inhibitor of MCJ expression protects liver from acetaminophen-induced liver injury at a time when N-acetylcysteine, the standard therapy, has no efficacy. We also show elevated levels of MCJ in the liver of patients with acetaminophen overdose. We suggest that MCJ may represent a therapeutic target to prevent and rescue liver injury caused by acetaminophen.
Indexed as
AcetaminophenAdolescentAdultAnimalsChemical and Drug Induced Liver InjuryDisease Models, AnimalDrug OverdoseElectron Transport Complex IFemaleGene Knockout TechniquesHepatocytesHSP40 Heat-Shock ProteinsHumansLiverMaleMiceAcetaminophenDNAJC15 protein, humanElectron Transport Complex IHSP40 Heat-Shock ProteinsMcj protein, mouseMitochondrial ProteinsMolecular ChaperonesRNA, Small InterferingRotenoneUncoupling Agents
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