Dr. Duvvuri's research objective is to elucidate the fundamental mechanisms of mitochondrial-mediated inflammation in the pathogenesis of autoimmune rheumatic diseases and to use this knowledge to discover therapeutic targets that will disrupt inflammatory properties of mitochondria thus ameliorating pathological inflammation driven by inflammatory mitochondria. Another key outcome of Dr. Duvvuri's research is identifying clinical biomarkers associated with mitochondria to better predict disease activity and severity to improve patients' clinical care and preventive treatment. Currently, major emphasis is on rheumatoid arthritis (RA), juvenile dermatomyositis (JDM), and systemic lupus erythematosus (SLE).
Mitochondria, owing to their prokaryotic origin, possess many bacteria-like features that include circular double-stranded DNA enriched with unmethylated CpG motifs (mtDNA), and mtDNA-encoded proteins with N-terminal formyl methionine group (a hallmark of prokaryotic-like protein machinery). Not surprisingly, mitochondrial-derived components are recognized as danger-associated molecular patterns given their ability to activate many innate immune sensors. Under healthy or physiological conditions, mitochondria are restricted within cells. In contrast, in conditions like SLE, recent studies suggest that dying cells may expel their inflammatory mitochondria into the circulation, suggesting a possibility of such a phenomenon in other disease conditions like RA and JDM with a mitochondrial involvement in disease pathogenesis. However, it is not known if patients with autoimmune rheumatic diseases, including SLE, have elevated levels of mitochondrial-derived components in their circulation, and their contribution to inflammation and thus to disease pathogenesis. Role of mtDNA and mitochondrial N-formyl methionine peptides are currently being explored in SLE and RA, respectively, with the following aims: (1) Mechanisms of mitochondrial DNA-mediated inflammation in SLE including the recognition and clearance of mtDNA (2) Mechanisms of mitochondrial N-formylated peptide-mediated neutrophil activation in RA.
The role of mitochondria in maintaining cellular calcium homeostasis is a fascinating area of its own in mitochondria' biology with significant implications for diseases like JDM where about 30% of patients develop ectopic or soft tissue calcification, calcinosis, leading to substantial morbidity. In these disease conditions, calcified mitochondria can function as a nidus to the mineralization process leading to pathological calcification. Currently, mitochondrial calcification mechanisms and their role in calcinosis that is characteristic of JDM are actively being investigated.