Mitochondrial DNA release and inflammation in mitochondrial disease pathogenesis

Primary mitochondrial diseases (PMDs) affect ∼1 in 4300 individuals, yet mitochondrial dysfunction is also a hallmark of common inherited and acquired disorders. Although advances in genomics now allow molecular diagnosis in the majority of mitochondrial diseases, treatment remains largely supportive, leading to progressive disability and early mortality. Despite progress in gene-modifying approaches, no approved therapies exist for the majority of mitochondrial diseases, and none of the recent trials has met its primary end point, underlining the urgent need for innovative therapeutic strategies. Patients with PMDs have highly variable phenotypes, further complicated by increased susceptibility to infections, chronic inflammation and metabolic abnormalities. Recently, it has become evident that certain mitochondrial pathologies, including the loss of mitochondrial membrane integrity, impaired mitochondrial DNA (mtDNA) maintenance, quality control defects or respiratory chain defects, result in the release of mtDNA into the cytosol. Infections or metabolic changes also trigger the release of mtDNA, leading to the activation of a sterile innate immune response and interferon signalling. Free mtDNA acts as a pathogen-associated molecular pattern (PAMP), activating innate immune pathways such as the cGAS-STING axis, initiating a sterile inflammatory response. This can be followed by the extracellular release of mtDNA to convey the inflammatory response systemically to communicate between cells or across organs. However, it is unclear whether these pathways worsen the disease phenotype (hyperinflammatory reaction) or, in contrast, rescue the symptoms owing to upregulation of compensatory pathways. In this review, we summarize recent advances in understanding the mechanism of mtDNA release and how it activates innate immune signalling in PMDs. We also discuss the implications for pathogenesis, clinical phenotypes and therapeutic development. Defining the role of circulating mitochondrial material as a biomarker or therapeutic target is a crucial step for precision medicine approaches in PMDs. These pathways might also have wider implications for common metabolic, inflammatory and neurodegenerative disorders with mitochondrial dysfunction.