Chemical-induced colitis lowers mitochondrial bioenergetic function in colonic tissue with minimal impacts on the proteome.

Dextran sulfate sodium (DSS) is widely used to chemically-induce both colitis and colorectal cancer when administered alongside azoxymethane (AOM). DSS functions by disrupting the colonic epithelial barrier, triggering widespread inflammation within the colon. While DSS is a valuable tool for studying colitis-related diseases, its impact on mitochondrial bioenergetics and the proteomic landscape of colonic tissue remains poorly understood. To assess the chronic effects of DSS-induced colitis, we administered three rounds of 3% DSS in drinking water (5-day treatment periods) to C57BL/6 J mice and analyzed resected colonic tissue from DSS-treated and control (non-DSS treated) mice. Longitudinally opened colon segments were cleaned and subjected to high-resolution respirometry and mass spectrometry-based proteomic profiling. DSS treatment led to a global lowering of mitochondrial respiration, with the most pronounced impairments observed in complex I-supported respiration. Proteomic analysis revealed that these functional deficits occurred largely independently of changes in the mitochondrial proteome, except for an apparent upregulation of NIPSNAP1, a mitophagy-related protein. However, lentiviral knockdown of NIPSNAP1 in HCT116 cells did not rescue the observed bioenergetic defects, suggesting it is not the primary driver. Collectively, our findings show that DSS impairs mitochondrial respiration in the colon, most notably at complex I, without major alterations to the mitochondrial proteome. Given the role of mitochondrial dysfunction in various diseases, these effects should be carefully considered when using DSS-based models to study colitis pathophysiology.