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Int J Biol Sci 2024; 20(7):2658-2685. doi:10.7150/ijbs.90835 This issue Cite

Research Paper

Mitochondrial Dysfunction by FADDosome Promotes Gastric Mucosal Injury in Portal Hypertensive Gastropathy

Yuelin Xiao^1*, Yiwang Zhang^2*, Kaiduan Xie¹, Xiaoli Huang¹, Xianzhi Liu¹, Jinni Luo¹, Siwei Tan^1✉

1. Department of Gastroenterology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, 510630, China.
2. Department of Pathology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, 510630, China.
* These authors contributed equally.

✉ Corresponding author: Siwei Tan, Department of Gastroenterology, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou 510630, China. Tel: +86-20-85253095; Email: tanswsysu.edu.cn; xiaodatou520com.

Abstract

Mucosal epithelial death is an essential pathological characteristic of portal hypertensive gastropathy (PHG). FADDosome can regulate mucosal homeostasis by controlling mitochondrial status and cell death. However, it remains ill-defined whether and how the FADDosome is involved in the epithelial death of PHG. The FADDosome formation, mitochondrial dysfunction, glycolysis process and NLRP3 inflammasome activation in PHG from both human sections and mouse models were investigated. NLRP3 wild-type (NLRP3-WT) and NLRP3 knockout (NLRP3-KO) littermate models, critical element inhibitors and cell experiments were utilized. The mechanism underlying FADDosome-regulated mitochondrial dysfunction and epithelial death in PHG was explored. Here, we found that FADD recruited caspase-8 and receptor-interacting serine/threonine-protein kinase 1 (RIPK1) to form the FADDosome to promote Drp1-dependent mitochondrial fission and dysfunction in PHG. Also, FADDosome modulated NOX2 signaling to strengthen Drp1-dependent mitochondrial fission and alter glycolysis as well as enhance mitochondrial reactive oxygen species (mtROS) production. Moreover, due to the dysfunction of electron transport chain (ETC) and alteration of antioxidant enzymes activity, this altered glycolysis also contributed to mtROS production. Subsequently, the enhanced mtROS production induced NLRP3 inflammasome activation to result in the epithelial pyroptosis and mucosal injury in PHG. Thus, the FADDosome-regulated pathways may provide a potential therapeutic target for PHG.

Keywords: portal hypertensive gastropathy, FADDosome, mitochondrial dysfunction, NLRP3 inflammasome, pyroptosis.

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