Mitochondrial oxidative stress — the imbalance between mitochondrial reactive oxygen species (ROS) generation and their elimination — has emerged as a shared feature of autoimmune disease, but its mechanisms and the barriers to treating it differ substantially between conditions. A narrative review published in Medicine Discovery examines rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis, integrating five regulatory pathways that maintain mitochondrial redox homeostasis (NRF2/KEAP1-ARE, AMPK/SIRT1/PGC-1α, SIRT3-mediated deacetylation, mitophagy, and the inflammasome) into a single network in which the adaptor p62/SQSTM1 couples mitophagy to NRF2 activation and the NAD⁺ pool jointly controls SIRT1 in the nucleus and SIRT3 in mitochondria. The review traces a bidirectional loop: oxidized mitochondrial DNA released into the cytoplasm triggers type I interferon signalling through cGAS-STING and is sensed by TLR9 in plasmacytoid dendritic cells, while mitochondrial components including cardiolipin and oxidized mitochondrial DNA can serve as autoantigens; in the reverse direction, TNF-α and IFN-γ inhibit the electron transport chain and increase ROS leakage, and regulatory T cell function is impaired. Disease-specific mechanisms are compared — a Warburg-type metabolic shift in rheumatoid arthritis synovial fibroblasts, defective mitophagy with interferon activation in lupus, and oligodendrocyte energy failure with blood-brain barrier disruption in multiple sclerosis. Therapeutic strategies reviewed include mitochondria-targeted antioxidants (MitoQ, SS-31), natural antioxidants, antioxidant nanoparticles, NOX4 and NLRP3 inhibitors, mitophagy regulators, and metabolic reprogramming, with the caveat that ROS also carry essential physiological signalling roles. The authors emphasise that agents targeting a single pathway may be compensated for by others, and that translation is limited by the absence of standardised clinical assays and validated biomarkers. The review is narrative rather than systematic and reports no new data.