Background/Purpose: We recently made the fundamental observation that mitochondrial extrusion is instrumental in mediating inflammation, autoimmunity and organ damage in lupus. Mitochondrial stress and mitochondrial autoantibodies have been reported in adult dermatomyositis (DM). However, the role of mitochondrial extrusion in juvenile DM is not known. One debilitating manifestation of chronic JDM is calcinosis, the formation of calcium deposits in soft tissue. Calcification may occur intracellularly in organelles, including mitochondria, but the role of mitochondrial calcification in JDM has not been investigated. In the current study, we investigated the role of mitochondrial calcification and extrusion in JDM pathogenesis, as well as the clinical utility of mitochondrial biomarkers.

Methods: Anti-mitochondrial autoantibodies, as well as cell-free mtDNA levels were analyzed in healthy children (HC, n=20), pediatric lupus (n=10), polymyositis (n=7), JDM patients (n=66), and RNP+ myositis (9), by a state-of-the-art flow cytometry technique as well as an in-house qPCR assay. In the Juvenile Myositis (JM) population, 74% were female, with a mean age of 11.3 years. The association of mitochondrial markers with clinical parameters was tested, including disease activity scores (DAS) for skin, muscle and total, the presence of calcinosis as well as Myositis Specific Antibodies (MSA). Electron microscopy of muscle surrounding calcifications was performed.

Results: As determined by electron microscopy, JDM children had evidence of mitochondrial calcification in affected muscle biopsies. Though phagocytosed by tissue-resident macrophages, the engulfed calcified mitochondria were not degraded, but remained in intracellular vesicles. Consistent with an important role of calcinosis in impaired mitochondrial extrusion and clearance, JM children with calcinosis had increased levels of cell-free mtDNA as compared to JM children without calcinosis and healthy children (p<0.05). Unexpectedly, levels of mtDNA were inversely correlated with DAS (r=-0.32, p=0.007) and the macrophage-derived inflammatory marker neopterin (r=-0.44, p=0.0003). Further, mitochondrial autoantibodies were elevated in JDM patients as compared to healthy individuals (40% vs 6%, p<0.001), with the highest frequency found in JDM children with p155/p140 (57%) and MDA5 (75%) MSA. For RNP+ myositis, the frequency was 42%. In JDM patients with no Myositis Associated Antibodies, only 18% of the children had anti-mitochondrial antibodies. Levels of anti-mitochondrial antibodies were associated with calcinosis (p<0.05), C4 levels (r=-0.63, p=0.002) and a bioassay for immune complexes (r=0.38, p=0.002). Children with SLE had increased anti-mitochondrial antibodies (90%, p<0.0001) as well as mtDNA (p<0.05).

Conclusion: Our results demonstrate a clear contribution of mitochondria in JDM pathogenesis and suggest mitochondrial calcification and subsequent extrusion and autoimmunity a novel, and potentially therapeutically targetable pathway. Further, mitochondrial biomarkers may offer clinical utility in monitoring disease activity and severity in Juvenile Myositis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mitochondrial-extrusion-and-autoimmunity-in-juvenile-dermatomyositis/