Mitochondrial dysfunction drives basal cell hyperplasia in eosinophilic oesophagitis

作者：Masaki Morimoto, Kento Kawasaki, Niamh McNamee, Samuel Flashner, Rieko Shimonosono, Masataka Shimonosono, Norihiro Matsuura, Yasuto Tomita, Wataru Hirose, Ryugo Teranishi, Takefumi Itami, Manti Guha, Pavithra Rajagopalan, Cecilia Martin, Hailey Golden, Diya Dhakal, Benjamin J. Wilkins, Andres J. Klein–Szanto, Kirk J. Wangensteen, Julian A. Abrams, Sydney Pomenti, David A. Katzka, Jianwen Que, Kelly A. Whelan, Amanda B. Muir, Hirohito Kita, Benjamin L. Wright, Alfred D. Doyle, Hiroshi Nakagawa, Uma M. Sachdeva · 发表于：Gut · 年份：2025 · DOI：10.1136/gutjnl-2024-334561 · 被引用次数：3 · 研究领域：Eosinophilic Esophagitis、Eosinophilic Disorders and Syndromes、IL-33, ST2, and ILC Pathways

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 mammal...