Mitochondrial Complex II in the regulation of immunopathology.

Mitochondrial complex II, succinate dehydrogenase (SDH), links the tricarboxylic acid cycle to the electron transport chain by oxidizing succinate to fumarate and reducing ubiquinone. This unusual position gives Complex II control over bioenergetics, redox state, succinate signaling, and chromatin regulation. In immune cells, Complex II regulates macrophage responses via the succinate-hypoxia-inducible factor-1α-IL-1β axis, T-cell proliferation, lineage commitment, and cytotoxicity. In target tissues of an aberrant immune attack, such as the intestinal epithelium and stem-cell compartments, SDHA loss lowers tissue tolerance, promotes inflammatory memory through succinate-driven epigenetic reprogramming, and amplifies immune-mediated injury. In tumors, SDH loss increases antigen presentation and their susceptibility to T-cell killing. Complex II, therefore, regulates immunopathology through its actions within both attacking immune cells and injured target tissues.