Circulating Mitochondrial DNA Stimulates Innate Immune Signaling Pathways to Mediate Acute Kidney Injury

Abstract

Mitochondrial dysfunction is increasingly considered as a critical contributor to the occurrence and progression of acute kidney injury (AKI). However, the mechanisms by which damaged mitochondria mediate AKI progression are multifactorial and complicated. Mitochondrial DNA (mtDNA) released from damaged mitochondria could serve as a danger-associated molecular pattern (DAMP) and activate the innate immune system through STING, TLR9, NLRP3, and some other adaptors, and further mediate tubular cell inflammation and apoptosis. Accumulating evidence has demonstrated the important role of circulating mtDNA and its related pathways in the progression of AKI, and regulating the proteins involved in these pathways may be an effective strategy to reduce renal tubular injury and alleviate AKI. Here, we aim to provide a comprehensive overview of recent studies on mtDNA-mediated renal pathological events to provide new insights in the setting of AKI.

Keywords: NLRP3; STING; TLR9; acute kidney injury; mitochondrial DNA.

Figure 1

Circulating mtDNA triggers the innate immune system through several mechanisms and mediates the pathogenesis of AKI. The occurrence of AKI is closely associated with mitochondrial dysfunction in renal tubular cells. Tubular mitochondrial damage leads to mtDNA leakage into cytosol and extracellular space. Circulating mtDNA binds with different DNA sensors and activates several innate immune signaling pathways such as cGAS–STING, TLR9-Myd88-NF-κB and NLRP3 inflammasome, leading to tubular inflammation and injury, which contributes to the progression of AKI. MtDNA, mitochondrial DNA; STING, stimulator of interferon genes; TBK1, TANK binding kinase 1; IKK, the IκB kinase; p, phosphorylation; IRF3, interferon regulatory factor 3; NF-κB, nuclear factor kappa B; TNF, tumor necrosis factor; TLR9, toll-like receptor 9; Myd88, myeloid differentiation factor 88; IRAK, interleukin 1 receptor associated kinase; Ub, ubiquitylation; TRAF6, TNF receptor associated factor 6; AIM2, absent in melanoma 2; IL, interleukin.