TY - JOUR
T1 - Mitochondrial dysfunction drives basal cell hyperplasia in eosinophilic oesophagitis
AU - Morimoto, Masaki
AU - Kawasaki, Kento
AU - McNamee, Niamh
AU - Flashner, Samuel
AU - Shimonosono, Rieko
AU - Shimonosono, Masataka
AU - Matsuura, Norihiro
AU - Tomita, Yasuto
AU - Hirose, Wataru
AU - Teranishi, Ryugo
AU - Itami, Takefumi
AU - Guha, Manti
AU - Rajagopalan, Pavithra
AU - Martin, Cecilia
AU - Golden, Hailey
AU - Dhakal, Diya
AU - Wilkins, Benjamin J.
AU - Klein-Szanto, Andres J.
AU - Wangensteen, Kirk J.
AU - Abrams, Julian A.
AU - Pomenti, Sydney
AU - Katzka, David A.
AU - Que, Jianwen
AU - Whelan, Kelly A.
AU - Muir, Amanda B.
AU - Kita, Hirohito
AU - Wright, Benjamin L.
AU - Doyle, Alfred D.
AU - Nakagawa, Hiroshi
AU - Sachdeva, Uma M.
N1 - © Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.
PY - 2025/9/8
Y1 - 2025/9/8
N2 - 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.
AB - 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.
KW - Animals
KW - Disease Models, Animal
KW - Eosinophilic Esophagitis/pathology
KW - Epithelial Cells/pathology
KW - Esophagus/pathology
KW - Humans
KW - Hyperplasia
KW - Mice
KW - Mitochondria/metabolism
KW - Omeprazole/pharmacology
KW - Organoids
KW - Proton Pump Inhibitors/pharmacology
UR - https://www.scopus.com/pages/publications/105011627456
U2 - 10.1136/gutjnl-2024-334561
DO - 10.1136/gutjnl-2024-334561
M3 - Article
C2 - 40701793
AN - SCOPUS:105011627456
SN - 0017-5749
VL - 74
SP - 1571
EP - 1588
JO - Gut
JF - Gut
IS - 10
ER -