Journal of advanced research · 2026
Mitochondria-associated endoplasmic reticulum membranes facilitate gastric epithelial injury in hypoxia-induced gastric mucosal lesions.
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Tan Siwei, Luo Jiajie, Ou Xingtong, Guo Xiaoning, Ke Bilun, Tan Shuyan
Аннотация
INTRODUCTION: Hypoxia following mucosal congestion in clinical practice causes a wide range of gastrointestinal symptoms and induces profound structural and functional perturbations in mitochondria-associated ER membranes (MAMs), which are subcellular compartments whose integrity and stability are regulated by FUN14 domain-containing protein 1 (FUNDC1).
OBJECTIVES: To investigate the effect of hypoxia-induced MAMs formation on gastric mucosal lesions in patients with severe hepatic disorders.
METHODS: Liver cirrhosis (LC) and hepatic failure (HF) were selected as representative severe hepatic diseases, and gastric mucosal tissues were collected. We applied the gastrointestinal symptom rating scale (GSRS) and endoscopic images to evaluate the possible relationship between gastrointestinal symptoms and mucosal lesions. Portal hypertension (PHT)-induced mouse models and hypoxia-induced cell models were also established. The roles of FUNDC1, hypoxia-induced MAMs formation and mitochondrial oxidative stress in mucosal epithelial injury were analyzed.
RESULTS: Patients with LC or HF frequently experienced gastrointestinal symptoms, which were correlated with the progression of gastric mucosal lesions. Hypoxia induced the upregulated expression of HIF-1α in gastric mucosal tissues, which was directly associated with the FUNDC1 promoter region, thereby increasing FUNDC1 gene transcription. Moreover, METTL3-mediated m6A methylation of FUNDC1 established a posttranscriptional regulatory layer to collectively drive upregulation of FUNDC1 expression. In addition, the increased level of FUNDC1 facilitated the formation of MAMs, drove a metabolic shift toward increased glycolysis, and elicited mitochondrial reactive oxygen species (mtROS) production. Ultimately, this increase in mtROS generation promoted NINJ1 oligomerization/activation to exacerbate gastric epithelial cell death and mucosal injury.
CONCLUSION: Under hypoxic conditions, FUNDC1-regulated MAMs formation and mitochondrial oxidative stress play pivotal roles in the development of gastric mucosal lesions.
OBJECTIVES: To investigate the effect of hypoxia-induced MAMs formation on gastric mucosal lesions in patients with severe hepatic disorders.
METHODS: Liver cirrhosis (LC) and hepatic failure (HF) were selected as representative severe hepatic diseases, and gastric mucosal tissues were collected. We applied the gastrointestinal symptom rating scale (GSRS) and endoscopic images to evaluate the possible relationship between gastrointestinal symptoms and mucosal lesions. Portal hypertension (PHT)-induced mouse models and hypoxia-induced cell models were also established. The roles of FUNDC1, hypoxia-induced MAMs formation and mitochondrial oxidative stress in mucosal epithelial injury were analyzed.
RESULTS: Patients with LC or HF frequently experienced gastrointestinal symptoms, which were correlated with the progression of gastric mucosal lesions. Hypoxia induced the upregulated expression of HIF-1α in gastric mucosal tissues, which was directly associated with the FUNDC1 promoter region, thereby increasing FUNDC1 gene transcription. Moreover, METTL3-mediated m6A methylation of FUNDC1 established a posttranscriptional regulatory layer to collectively drive upregulation of FUNDC1 expression. In addition, the increased level of FUNDC1 facilitated the formation of MAMs, drove a metabolic shift toward increased glycolysis, and elicited mitochondrial reactive oxygen species (mtROS) production. Ultimately, this increase in mtROS generation promoted NINJ1 oligomerization/activation to exacerbate gastric epithelial cell death and mucosal injury.
CONCLUSION: Under hypoxic conditions, FUNDC1-regulated MAMs formation and mitochondrial oxidative stress play pivotal roles in the development of gastric mucosal lesions.