Mitochondrial homeostasis and aging: the mtDNA-cGAS-STING axis

Abstract

Aging and its associated diseases have become an increasingly severe global health challenge, not only significantly exacerbating the global disease burden but also posing a continuous threat to public health systems worldwide. During the aging process, the aberrant release of endogenous mitochondrial DNA (mtDNA) is a key trigger for the activation of the cGAS–STING innate immune pathway. Existing research has confirmed that the overactivation of the cGAS–STING pathway is the core molecular mechanism driving the senescence-associated secretory phenotype (SASP), chronic inflammation, and organ functional decline. Notably, the mechanisms of mtDNA release and the activation characteristics of the cGAS–STING pathway exhibit significant organ-specificity. Different tissues mediate mtDNA leakage through specific pathways, such as mitochondrial permeability transition, oxidative damage, and defective mitophagy, thereby differentially regulating downstream inflammatory signals. Given the central driving role of the aberrantly activated mtDNA-cGAS-STING axis in age-related organ damage, targeting this pathway has emerged as a promising therapeutic strategy for the systemic mitigation of aging-associated chronic inflammation. This review systematically elucidates the molecular basis of the mtDNA-cGAS-STING pathway, delves into its organ-specific activation mechanisms, and critically evaluates current intervention frameworks and clinical prospects, aiming to provide a theoretical basis and innovative perspectives for the precision prevention and clinical management of age-related diseases.