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Mitochondrial oxidative stress under hypoxia promotes gastric mucosal injury in portal hypertensive gastropathy

  • Authors:
    • Jiajie Luo
    • Kaiduan Xie
    • Xingtong Ou
    • Siwei Tan
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510630, P.R. China
    Copyright: © Luo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 29
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    Published online on: January 7, 2026
       https://doi.org/10.3892/br.2026.2102
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Abstract

Hypoxia, which represents a key pathological feature of gastric mucosal disorders, exacerbates mitochondrial oxidative stress through dysregulated cellular responses. However, the underlying mechanism of mitochondrial oxidative stress under hypoxia during gastric mucosal epithelial injury in portal hypertensive gastropathy (PHG) is not fully understood. To assess the impact of mitochondrial oxidative stress under hypoxic conditions during gastric mucosal epithelial injury in the PHG, mucosal tissues from patients with PHG and healthy individuals were collected. Furthermore, portal hypertension (PHT)‑induced mouse PHG models and hypoxia‑induced cell models were established. The roles of hypoxia‑induced mitochondrial oxidative stress and glycolytic reprogramming in gastric mucosal epithelial injury were analysed. The findings demonstrated that mitochondrial oxidative stress is significantly elevated under hypoxic conditions, leading to an increase in reactive oxygen species (ROS) generation. This process contributes to gastric mucosal epithelial damage in both patients with PHG and mice with PHT. Notably, treatment with the ROS scavenger Mito‑TEMPO reduced hypoxia‑induced gastric mucosal injury in mice with PHT and mitigated cellular damage caused by hypoxia in a normal human gastric mucosal epithelial cell line (GES‑1). Mitochondrial oxidative stress was shown to be associated with lactate dehydrogenase A upregulation, impaired ATP production and increased lactic acid release in gastric epithelial cells, all of which contribute to epithelial injury in the PHG. Therefore, hypoxia‑induced mitochondrial oxidative stress has emerged as a promising therapeutic target for PHG.
View Figures

Figure 1

Hypoxia participates in gastric
mucosal injury of PHG in both humans and mice. (A) Representative
gastric endoscopic images and H&E-stained sections of gastric
mucosa from patients with PHG were compared with those from healthy
individuals (as Healthy). Scale bar, 50 µm for H&E images.
Hypoxyprobe-1 staining (green) was performed on primary gastric
mucosal epithelial cells isolated from both PHG patients and
healthy controls. Nuclei (blue) were counterstained with DAPI.
Scale bar, 10 µm. (B) Gross image, H&E staining, and
Hypoxyprobe-1 immunohistochemical staining (brown) of the gastric
mucosa in the mice with PHT compared with that in the control mice.
Scale bar, 50 µm for H&E and IHC images. (C) Quantitative
analysis of Hypoxyprobe-1 fluorescence intensity from (A), n=10 per
group; *P<0.05. (D) Mucosal injury index analysis in
the murine models is presented, n=6 per group;
*P<0.05. (E) The percentage of the
Hypoxyprobe-1-positive area corresponding to the gastric injury
index of PHT mouse models was analyzed. n=6 per group;
*P<0.05 vs. the group with a gastric injury index of
0. PHG, portal hypertensive gastropathy; H&E, hematoxylin and
eosin; DAPI, 4',6-diamidino-2-phenylindole dihydrochloride; PHT,
portal hypertension; CTRL, control.

Figure 2

Enhanced mitochondrial oxidative
stress is identified in the gastric mucosa epithelia of patients
with PHG. (A) Volcano plot of differentially expressed genes in the
PHG group compared with those in the healthy individual group. GO
pathway enrichment of signalling pathways according to the
microarray analysis, n=3 in each group. (B) TEM analysis of
mitochondrial morphological changes (Scale bar, 0.5 µm), 4-HNE
immunohistochemical staining (Scale bar=50 µm), and MitoSox
fluorescent staining of primary gastric mucosal epithelial cells
were performed in the gastric mucosal tissues from both healthy
individuals (as Healthy) and patients with PHG (as PHG). Nuclei
(blue) were counterstained with Hoechst 33258 in fluorescence
staining. Scale bar, 10 µm. (C) The quantitative values of
mitochondrial average area and mitochondrial length-to-width ratio
obtained from TEM were presented. The MitoSox fluorescence
intensity and 4-HNE staining quantification from (B) were also
determined, n=10 per group; *P<0.05. PHG, portal
hypertensive gastropathy; GO, Gene Ontology; TEM, transmission
electron microscopy.

Figure 3

Mitochondrial oxidative stress is
enhanced in the in vivo and in vitro models. (A) TEM
analysis of mitochondrial morphological changes (Scale bar, 0.5
µm), MitoSox staining of primary gastric mucosal epithelial cells
(Scale bar, 10 µm), and immunohistochemical staining for 4-HNE were
performed in the gastric mucosal tissues from both control and PHT
group mice (Scale bar, 50 µm). Nuclei (blue) were counterstained
with Hoechst 33258 in MitoSox staining.(B) The quantitative
analysis of ROS fluorescence in primary gastric mucosal epithelial
cells and mt 8-OHdG concentration were determined. The MitoSox
fluorescence intensity and the quantitative analysis of 4-HNE
staining from (A) were also analyzed. n=6 per group;
*P<0.05. (C) Morphology and MitoSox fluorescence
staining of GES-1 cells under normoxic and hypoxic conditions.
Nuclei (blue) were counterstained with Hoechst 33258 in MitoSox
staining. Scale bars, 25 µm (upper panels) and 10 µm (lower
panels). (D) The mt 8-OHdG concentration and the quantitative
analysis of MitoSox fluorescence intensity in GES-1 cells under
normoxic and hypoxic conditions are shown. n=6 per group;
*P<0.05. TEM, transmission electron microscopy; PHT,
portal hypertension; mt 8-OhdG, mitochondrial 8-OhdG; CTRL,
control.

Figure 4

ROS scavenger Mito-TEMPO attenuates
gastric mucosal epithelial injury from in vivo and in
vitro models. (A) H&E staining of gastric mucosal tissues
and analysis of gastric mucosal injury index in the mouse model
treated with Mito-TEMPO or not. Scale bar, 100 µm. n=6 per group.
*P<0.05 vs. the control group; #P<0.05
vs. the PHT group without Mito-TEMPO. (B) The morphology and
H&E staining of GES-1 cell under normoxic and hypoxic
conditions treated with Mito-TEMPO (or not) are shown. The relative
cell viability analyzed by Cell Counting Kit-8 were also
determined. Scale bar, 25 µm. n=6 per group. *P<0.05
vs. the normoxia group; #P<0.05 vs. the hypoxia group
without Mito-TEMPO. ROS, reactive oxygen species; H&E,
hematoxylin and eosin; PHT, portal hypertension; CTRL, control.

Figure 5

Mitochondrial dysfunction is
associated with the glycolytic LDHA upregulation in PHG. (A) The
heatmap analysis of differentially expressed genes between normal
gastric mucosa (healthy individuals-indicated as Healthy) and
gastric mucosa from patients with PHG (indicated as PHG) revealed
increased expression of LDHA and other genes involved in the
glycolytic metabolic pathway. (B) The glycolytic metabolic pathway
is presented. (C) The fold changes and P-values of the indicated
mRNAs in PHG tissues relative to those in normal (healthy
individuals-indicated as Healthy) tissues from the microarray
experiment are presented. (D) Immunohistochemical (brown) or
immunofluorescence (green) staining and quantitative analysis of
LDHA in the clinical tissue samples (n=10 per group), mouse models
(n=6 per group), and cellular hypoxia models (n=6 per group).
Nuclei (blue) were counterstained with DAPI in immunofluorescence
staining. Scale bars, 50 µm (IHC images) and 25 µm (IF images).
*P<0.05. (E) Western blotting detection of LDHA
protein expression levels in clinical tissue samples, mouse models,
and cellular hypoxia models. Ratios of densitometric units of
normalized LDHA/β-actin were determined from western blotting. n=6
per group. *P<0.05. PHG, portal hypertensive
gastropathy; LDHA, lactate dehydrogenase A; DAPI,
4',6-diamidino-2-phenylindole dihydrochloride; CTRL, control; PHT,
portal hypertension.

Figure 6

Mitochondrial oxidative stress in PHG
is accompanied by ATP production and promotes lactic acid
production. (A) Principal component analysis of metabolic
components in gastric mucosal tissues from the control group and
mice with PHT. n=4 per group. (B) Stacked bar plots comparing the
relative abundance of amino acid metabolism, carbohydrate
metabolism, and organic acid metabolism in the gastric mucosal
tissues between the control group and PHT mice. (C) Volcano plot
and bar chart analyses of carbohydrate metabolism biomarkers in the
indicated gastric mucosal tissues. (D) The ATP concentrations in
the clinical tissue samples (n=10 per group), murine models (n=6
per group), and cellular hypoxia models (n=6 per group) were
analyzed. *P<0.05. (E) The lactic acid concentrations
in clinical tissue samples (n=10 per group), mouse models (n=6 per
group), and cellular hypoxia models (n=6 per group) were assessed.
*P<0.05. (F) H&E staining and gastric mucosal
injury index scores in the indicated mouse models (treated with
lactate dehydrogenase A inhibitor oxamic acid sodium or not) were
determined. Scale bar, 100 µm. n=6 per group. *P<0.05
vs. the control group; #P<0.05 vs. the PHT group
without oxamic acid sodium. (G) H&E staining of the GES-1 cell
models under normoxia and hypoxia following oxamic acid sodium
administration. Cell viability from the indicated groups was also
analyzed by Cell Counting Kit-8 assay. Scale bar, 50 µm. n=6 per
group. *P<0.05 vs. the normoxia group;
#P<0.05 vs. the hypoxia group without oxamic acid
sodium. PHG, portal hypertensive gastropathy; PHT, portal
hypertension; H&E, hematoxylin and eosin; CTRL, control; PBS,
phosphate-buffered saline.

Figure 7

Schematic diagram of mitochondrial
oxidative stress following hypoxia in the gastric mucosal
epithelial injury of PHG. The graphical abstract is shown. PHG,
portal hypertensive gastropathy; LDHA, lactate dehydrogenase A;
ROS, reactive oxygen species.
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Copy and paste a formatted citation
Spandidos Publications style
Luo J, Xie K, Ou X and Tan S: Mitochondrial oxidative stress under hypoxia promotes gastric mucosal injury in portal hypertensive gastropathy. Biomed Rep 24: 29, 2026.
APA
Luo, J., Xie, K., Ou, X., & Tan, S. (2026). Mitochondrial oxidative stress under hypoxia promotes gastric mucosal injury in portal hypertensive gastropathy. Biomedical Reports, 24, 29. https://doi.org/10.3892/br.2026.2102
MLA
Luo, J., Xie, K., Ou, X., Tan, S."Mitochondrial oxidative stress under hypoxia promotes gastric mucosal injury in portal hypertensive gastropathy". Biomedical Reports 24.2 (2026): 29.
Chicago
Luo, J., Xie, K., Ou, X., Tan, S."Mitochondrial oxidative stress under hypoxia promotes gastric mucosal injury in portal hypertensive gastropathy". Biomedical Reports 24, no. 2 (2026): 29. https://doi.org/10.3892/br.2026.2102
Copy and paste a formatted citation
x
Spandidos Publications style
Luo J, Xie K, Ou X and Tan S: Mitochondrial oxidative stress under hypoxia promotes gastric mucosal injury in portal hypertensive gastropathy. Biomed Rep 24: 29, 2026.
APA
Luo, J., Xie, K., Ou, X., & Tan, S. (2026). Mitochondrial oxidative stress under hypoxia promotes gastric mucosal injury in portal hypertensive gastropathy. Biomedical Reports, 24, 29. https://doi.org/10.3892/br.2026.2102
MLA
Luo, J., Xie, K., Ou, X., Tan, S."Mitochondrial oxidative stress under hypoxia promotes gastric mucosal injury in portal hypertensive gastropathy". Biomedical Reports 24.2 (2026): 29.
Chicago
Luo, J., Xie, K., Ou, X., Tan, S."Mitochondrial oxidative stress under hypoxia promotes gastric mucosal injury in portal hypertensive gastropathy". Biomedical Reports 24, no. 2 (2026): 29. https://doi.org/10.3892/br.2026.2102
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