Mitochondrial DNA (mtDNA) accelerates oxygen-glucose deprivation-induced injury of proximal tubule epithelia cell via inhibiting NLRC5

•OGD/R contributed to the production mtDNA.•mtDNA aggravated inflammation and apoptosis.•mtDNA promoted NLRC5 expression. The high morbidity and mortality associated with acute kidney injury (AKI) are global health concerns. AKI is commonly attributed to ischemia/reperfusion injury (IRI), a condition characterized by activation of inflammatory responses and mitochondrial dysfunction. Nonetheless, mitochondrial DNA (mtDNA) has the potential to induce renal IRI. This study aimed to elucidate the mechanism and function of mtDNA in HK-2 cells that had been exposed to oxygen-glucose deprivation/reperfusion (OGD/R) and in renal IRI mice. OGD/R was discovered to induce an increase in the amount of mtDNA in HK-2 cells. Moreover, our study demonstrated that mtDNA facilitated cellular apoptosis and inflammation in vivo and in vitro. Given the potential role of inflammation in OGD/R, we investigated the effect of mtDNA on various signaling pathways associated with inflammation. Western blot analysis demonstrated that mtDNA significantly upregulated NLRC5/TAP1 signaling. Furthermore, the upregulation of NLRC5 and TAP1 expression induced by mtDNA was reversed when NLRC5 was inhibited. It is worth mentioning that the loss of NLRC5 effectively nullified the beneficial effects of mtDNA on inflammation and cell apoptosis induced by OGD/R. In addition, in renal IRI mice, mtDNA treatment also aggravated inflammation and kidney damage, and increased the NLRC5 levels in kidney tissues. These results suggested that NLRC5 acts as an intermediary between mtDNA and the pathogenicity of renal IRI. In summary, this study provides evidence that mtDNA promotes apoptosis and inflammation in OGD/R treated HK-2 cells and renal IRI mice through upregulating NLRC5 levels.