Mitochondrial dysfunction in patients with celiac disease: A multidimensional study

Abstract

BACKGROUND

Celiac disease (CeD) is an autoimmune enteropathy triggered by gluten, but its pathogenesis remains unclear. One possible mechanism is mitochondrial dysfunction; however, no structural or functional evidence of mitochondrial damage in the intestinal epithelium of CeD patients has been reported.

AIM

To identify whether there is any structural or functional mitochondrial damage in the duodenal mucosa of active CeD patients.

METHODS

In this pilot study, 18 individuals with active CeD were enrolled alongside 18 age- and sex-matched healthy controls. Markers of metabolic energy (adenosine triphosphate, L-lactate), apoptosis (caspase 9), and oxidative stress (malondialdehyde, 4-hydroxynonenal, superoxide dismutase, glutathione peroxidase) were quantified using commercial-grade biochemical assay kits. Transmission electron microscopy was utilized to examine ultrastructural variations of mitochondria in intestinal epithelial cells. The expression levels of mitochondrial variations-related proteins (MFN1, MFN2, OPA1, DRP1, FIS1) were assessed using western blotting in duodenal mucosal samples. Quantitative real-time polymerase chain reaction was utilized to calculate mitochondrial DNA copy number in duodenal tissue samples. Clinical hematological and biochemical parameters were also assessed for exploratory correlation analyses.

RESULTS

Transmission electron microscopy revealed notable ultrastructural changes in the mitochondria of intestinal epithelial cells in CeD patients, including swelling of the organelles, disorganized or disrupted cristae, and vacuolization. In comparison to healthy subjects, individuals with CeD showed pronounced alterations in intestinal mucosal mitochondrial energy balance, characterized by decreased adenosine triphosphate production alongside increased L-lactate concentrations. Superoxide dismutase and glutathione peroxidase activities were significantly reduced, and malondialdehyde and 4-hydroxynonenal levels were significantly elevated, indicating a dramatic change towards oxidative stress. Western blot analysis simultaneously identified changed expression of mitochondrial dynamics proteins in CeD patients with a significant decrease in the expression of MFN1 and MFN2 (fusion proteins) and a significant increase in the expression of DRP1, p-DRP1 (active isoform of DRP1), and FIS1 (fission proteins). The copy number of the mitochondrial DNA using quantitative real-time polymerase chain reaction was also considerably lower among CeD patients than their healthy counterparts (P < 0.05). Correlation analysis suggests potential associations between mitochondrial parameters and hematological abnormalities.

CONCLUSION

This work is the first comprehensive evidence of structural and functional mitochondrial damage in the duodenal mucosa of individuals with CeD. The results offer new experimental data on the study of the pathogenesis of CeD and a useful theoretical basis to develop new therapeutic options that will target the mitochondria.

Keywords: Celiac disease; Mitochondria; Oxidative stress; Energy metabolism; Mitochondrial dynamics proteins

Core Tip: This study provides the first multidimensional evidence of structural and functional mitochondrial damage in the duodenal mucosa of patients with active celiac disease, including ultrastructural abnormalities, impaired energy metabolism, increased oxidative stress, imbalanced mitochondrial dynamics, and reduced mitochondrial DNA copy number. These findings offer new experimental insights into the pathogenesis of celiac disease.