Mitochondrial Dysfunction in Inflammatory Skin Diseases: Mechanisms, Biomarkers, and Emerging Therapeutic Strategies

Mitochondrial dysfunction critically underpins the pathogenesis of inflammatory skin diseases such as psoriasis, vitiligo, atopic dermatitis, and impaired wound healing. This comprehensive review synthesizes recent evidence to elucidate mechanisms, including compromised bioenergetics, excessive reactive oxygen species (ROS), mitochondrial DNA (mtDNA) damage, and aberrant mitochondrial dynamics. Distinct from prior work, this analysis uncovers novel findings: mtDNA acts as a damage-associated molecular pattern, activating cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathways to drive type I interferon in vitiligo and IL-17A in psoriasis; succinate-mediated immune-metabolic signaling amplifies type 2 inflammation in atopic dermatitis; and subclinical mitochondrial impairments in non-lesional skin serve as early indicators of disease susceptibility across these conditions. Preclinical studies have shown that emerging therapies, including antioxidants (e.g., NMN), mitochondrial modulators (e.g., SS31), senotherapeutics, and mitochondrial transplantation, are promising strategies for restoring cellular function. Future research should focus on multi-omics to dissect mitochondrial-epigenetic interactions, validate mitochondrial metabolites like succinate as diagnostic biomarkers, and explore synergistic combination therapies. This integrative framework of mitochondrial-driven pathology provides fresh perspectives to advance diagnostic and therapeutic innovation in dermatology.