Mitochondrial DNA Abnormalities in Idiopathic Inflammatory Myopathies: Innate Immune Signaling and Therapeutic Prospects

Mitochondrial DNA (mtDNA) encodes essential components of oxidative phosphorylation and can stimulate innate immunity when released from mitochondria. Its genetic and immunological functions provide a rationale for investigating mtDNA abnormalities in idiopathic inflammatory myopathies (IIMs), where muscle dysfunction and inflammation coexist. Large-scale deletions and depletion have been documented in inclusion body myositis and polymyositis with mitochondrial pathology, while dermatomyositis studies reveal regional depletion and oxidative modifications in distinct biological compartments. These findings raise the possibility that mtDNA abnormalities contribute to both impaired mitochondrial function and inflammatory signaling. This review integrates subtype-specific findings with mechanistic studies of mtDNA release, DNA sensing, and inflammasome activation in IIM-related and non-IIM systems. It evaluates the evidence for mtDNA-based biomarkers and therapies targeting mitochondrial injury or downstream inflammation. The reported clinical benefits do not establish mtDNA-specific therapeutic effects. Defining how mitochondrial genome abnormalities and inflammatory signaling interact within each subtype is a priority for biomarker validation and therapeutic research.