Increasing evidence showed that mitochondrial DNA (mtDNA), as a part of mitochondrial damage-associated molecular patterns (DAMPs), induces an immune response and inflammation in immune, as well as in cells of nonnimmune origin. As insulin resistance and type 2 diabetes are characterized by a persistent chronic inflammation, the aim if this study was to evaluate if mtDNA DAMPs induce an inflammatory responses in skeletal muscle cells and induce insulin resistance both in vitro and vivo. In vitro study showed that exogenous mtDNA fragments induced TLR9-mediated NF-κB activation in primary muscle cells. Also, we found that mtDNA DAMPs and palmitate increased TLR9 content in muscle cells. Furthermore, mtDNA DAMPs reduced insulin signaling and insulin stimulated glucose uptake in primary muscle cells. Importantly, administration of exogenous mtDNA DAMPs induced inflammatory signaling, hyperglycemia and insulin resistance in vivo, providing a direct causative role for mtDNA DAMPs in the development of insulin resistance. Parallel studies in vivo showed that high fat diet-induced insulin resistant mice (Yuzefovych et al, 2013, PLOS One) have elevated circulating mtDNA DAMPs contents which were associated with increased mtDNA damage in skeletal muscle and liver, increased oxidative stress and content of TLR9 in skeletal muscle. Collectively, this study identifies a novel role for mtDNA as a pro-inflammatory molecule which promotes insulin resistance. Ultimately, this can provide new clinical implications both to design novel therapeutic strategies and cost-effective biomarkers of insulin resistance progression.
L. Yuzefovych: None. V.M. Pastukh: None. L. Rachek: None.