P.80 Respiratory chain dysfunction in dermatomyositis is associated with mitochondrial DNA depletion

Abstract

Patients with dermatomyositis suffer from reduced aerobic metabolism contributing to impaired muscle function, which has been linked to cytochrome c oxidase (COX) deficiency in muscle tissue. This mitochondrial respiratory chain dysfunction is typically seen in perifascicular regions, which also show the most intense inflammatory reaction along with capillary loss and muscle fiber atrophy. The objective of this study was to investigate the pathobiology of the oxidative phosphorylation deficiency in dermatomyositis. Muscle biopsy specimens with perifascicular COX deficiency from five juveniles and seven adults with early untreated dermatomyositis were investigated. Immunohistochemical analyses of subunits in the respiratory chain were performed including complex I (subunit NDUFB8), complex II (succinate dehydrogenase, subunit SDHB) and complex IV (COX, subunit MTCO1). The results showed a profound deficiency of complex I and IV in the perifascicular regions with enzyme histochemical COX deficiency, whereas succinate dehydrogenase activity and complex II were preserved. In situ hybridization of mitochondrial RNA showed depletion of mitochondrial DNA (mtDNA) transcripts in the perifascicular regions. Analysis of mtDNA by next generation deep sequencing and quantitative PCR in affected muscle regions showed an overall reduction of mtDNA copy number particularly in the perifascicular regions. In conclusion, the respiratory chain dysfunction in dermatomyositis muscle is associated with mtDNA depletion causing deficiency of complex I and IV which are partially encoded by mtDNA, whereas complex II which is entirely nuclear gene encoded is preserved. The depletion of mtDNA indicates a perturbed replication of mtDNA partially explaining the muscle pathology and the disturbed aerobic metabolism.