Mitochondrial Dysfunction in Ulcerative Colitis: Pathogenic Mechanisms and Novel Therapeutics

Ulcerative colitis (UC) is a chronic inflammatory bowel disease driven by a complex interplay of mitochondrial dysfunction. These defects impair energy production, increases oxidative stress, and disrupts immune balance. Here we review three therapeutic classes that target mitochondrial pathways: antioxidants, metabolic modulators, and microbiota-directed strategies. In UC, mitochondrial dysfunction creates a self-perpetuating cycle through metabolic-immune crosstalk, the leakage of mitochondrial DNA, and the redistribution of cardiolipin. Moreover, the gut microbiota and mitochondria engage in bidirectional crosstalk that amplifies intestinal inflammation. Encouragingly, agents that restore mitochondrial function have shown therapeutic benefit in preclinical and early clinical studies. Notable examples include the mitochondria-targeted antioxidant MitoQ (currently in a Phase 2b trial for UC), ClpP (caseinolytic protease P) activators that reprogram T-cell metabolism, and engineered probiotics that deplete pro-inflammatory succinate. This review synthesizes current evidence on mitochondrial dysfunction in UC, bridging molecular mechanisms, immune-metabolic interactions, and emerging therapeutics to propose a new treatment paradigm centered on mitochondrial restoration.