{
  "abstract": "Background Eosinophilic oesophagitis (EoE) is a food allergen-induced inflammatory disorder characterised by interleukin (IL)-13-mediated oesophageal inflammation and epithelial basal cell hyperplasia (BCH). The role of mitochondria in EoE pathogenesis remains elusive.Design Prompted by single cell transcriptomics data, we interrogated the role of mitochondria in EoE pathobiology using patient biopsies, EoE-mouse models and oesophageal epithelial cells grown in monolayer and three-dimensional (3D) organoid cultures treated with EoE-relevant cytokines. 3D organoids and EoE-bearing mice were treated with omeprazole—a proton-pump inhibitor used as first-line EoE therapy. We performed CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) interference in mouse organoids to identify the key mitochondrial regulatory genes whose depletion may lead to BCH. We analysed mitochondrial membrane potential, mass and superoxide production by flow cytometry, cellular oxygen consumption by respirometry, mitochondrial structures and perturbation of cellular energy homeostasis by immunoblotting. Results  Mitochondrial dysfunction appeared to be a hallmark of EoE-related BCH where mitochondrial structural damage was associated with impaired oxidative respiratory capacity, elevation of mitochondrial superoxide and decreased adenosine triphosphate (ATP) production, as corroborated by activation of the adenosine monophosphate (AMP) -activated protein kinase and suppression of mammalian target-of-rapamycin signalling. Depletion of PGC1A, the master regulator of mitochondria biogenesis, recapitulated EoE-related BCH, suggesting that mitochondrial dysfunction drives BCH. Further, omeprazole alleviated mitochondrial damage and dysfunction in EoE-related BCH modelled in mice and patient-derived organoids. Conclusion Mitochondrial dysfunction is tightly linked to perturbation of redox homeostasis in EoE-related BCH, which is promoted by IL-13 and reversible with omeprazole treatment.",
  "authors": [
    {
      "affiliations": [
        "Columbia University Herbert Irving Comprehensive Cancer Center, New York, New York, USA"
      ],
      "name": "Masaki Morimoto"
    },
    {
      "affiliations": [
        "Columbia University Herbert Irving Comprehensive Cancer Center, New York, New York, USA"
      ],
      "name": "Kento Kawasaki"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital, Boston, Massachusetts, USA"
      ],
      "name": "Niamh McNamee"
    },
    {
      "affiliations": [
        "Columbia University Herbert Irving Comprehensive Cancer Center, New York, New York, USA"
      ],
      "name": "Samuel Flashner"
    },
    {
      "affiliations": [
        "Columbia University Herbert Irving Comprehensive Cancer Center, New York, New York, USA"
      ],
      "name": "Rieko Shimonosono"
    },
    {
      "affiliations": [
        "Columbia University Herbert Irving Comprehensive Cancer Center, New York, New York, USA"
      ],
      "name": "Masataka Shimonosono"
    },
    {
      "affiliations": [
        "Columbia University Herbert Irving Comprehensive Cancer Center, New York, New York, USA"
      ],
      "name": "Norihiro Matsuura"
    },
    {
      "affiliations": [
        "Columbia University Herbert Irving Comprehensive Cancer Center, New York, New York, USA"
      ],
      "name": "Yasuto Tomita"
    },
    {
      "affiliations": [
        "Columbia University Herbert Irving Comprehensive Cancer Center, New York, New York, USA"
      ],
      "name": "Wataru Hirose"
    },
    {
      "affiliations": [
        "Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Ryugo Teranishi"
    },
    {
      "affiliations": [
        "Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Takefumi Itami"
    },
    {
      "affiliations": [
        "Columbia University Herbert Irving Comprehensive Cancer Center, New York, New York, USA"
      ],
      "name": "Manti Guha"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital, Boston, Massachusetts, USA"
      ],
      "name": "Pavithra Rajagopalan"
    },
    {
      "affiliations": [
        "Columbia University Herbert Irving Comprehensive Cancer Center, New York, New York, USA",
        "Division of Digestive & Liver Diseases, Department of Medicine, Columbia University, New York, New York, USA",
        "Digestive & Liver Disease Research Center, Columbia University, New York, New York, USA"
      ],
      "name": "Cecilia Martin"
    },
    {
      "affiliations": [
        "Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Hailey Golden"
    },
    {
      "affiliations": [
        "Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Diya Dhakal"
    },
    {
      "affiliations": [
        "Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Benjamin J Wilkins"
    },
    {
      "affiliations": [
        "Histopathology Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Andres J Klein-Szanto"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA"
      ],
      "name": "Kirk J Wangensteen"
    },
    {
      "affiliations": [
        "Columbia University Herbert Irving Comprehensive Cancer Center, New York, New York, USA",
        "Division of Digestive & Liver Diseases, Department of Medicine, Columbia University, New York, New York, USA",
        "Digestive & Liver Disease Research Center, Columbia University, New York, New York, USA"
      ],
      "name": "Julian A Abrams"
    },
    {
      "affiliations": [
        "Division of Digestive & Liver Diseases, Department of Medicine, Columbia University, New York, New York, USA"
      ],
      "name": "Sydney Pomenti"
    },
    {
      "affiliations": [
        "Columbia University Herbert Irving Comprehensive Cancer Center, New York, New York, USA",
        "Division of Digestive & Liver Diseases, Department of Medicine, Columbia University, New York, New York, USA"
      ],
      "name": "David A Katzka"
    },
    {
      "affiliations": [
        "Columbia University Herbert Irving Comprehensive Cancer Center, New York, New York, USA",
        "Division of Digestive & Liver Diseases, Department of Medicine, Columbia University, New York, New York, USA"
      ],
      "name": "Jianwen Que"
    },
    {
      "affiliations": [
        "Fels Cancer Institute for Personalized Medicine, Department of Cancer & Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Kelly A Whelan"
    },
    {
      "affiliations": [
        "Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA",
        "Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Amanda B Muir"
    },
    {
      "affiliations": [
        "Division of Allergy, Asthma, and Clinical Immunology, Mayo Clinic Arizona, Scottsdale, Arizona, USA"
      ],
      "name": "Hirohito Kita"
    },
    {
      "affiliations": [
        "Division of Allergy, Asthma, and Clinical Immunology, Mayo Clinic Arizona, Scottsdale, Arizona, USA"
      ],
      "name": "Benjamin L Wright"
    },
    {
      "affiliations": [
        "Division of Allergy, Asthma, and Clinical Immunology, Mayo Clinic Arizona, Scottsdale, Arizona, USA"
      ],
      "name": "Alfred D Doyle"
    },
    {
      "affiliations": [
        "Columbia University Herbert Irving Comprehensive Cancer Center, New York, New York, USA",
        "Division of Digestive & Liver Diseases, Department of Medicine, Columbia University, New York, New York, USA",
        "Digestive & Liver Disease Research Center, Columbia University, New York, New York, USA"
      ],
      "name": "Hiroshi Nakagawa"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital, Boston, Massachusetts, USA",
        "Thoracic Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA"
      ],
      "name": "Uma M Sachdeva"
    }
  ],
  "title": "Mitochondrial dysfunction drives basal cell hyperplasia in eosinophilic oesophagitis",
  "uid": "de7e73de-c3bc-5e4b-a2f0-05c39fdbaf57"
}