Abstract
The integrity and function of mitochondria are essential for normal kidney physiology. Mitochondrial DNA (mtDNA) has been widely a concern in recent years because its abnormalities may result in disruption of aerobic respiration, cellular dysfunction, and even cell death. Particularly, aberrant mtDNA copy number (mtDNA-CN) is associated with the development of acute kidney injury and chronic kidney disease, and urinary mtDNA-CN shows the potential to be a promising indicator for clinical diagnosis and evaluation of kidney function. Several lines of evidence suggest that mtDNA may also trigger innate immunity, leading to kidney inflammation and fibrosis. In mechanism, mtDNA can be released into the cytoplasm under cell stress and recognized by multiple DNA-sensing mechanisms, including Toll-like receptor 9 (TLR9), cytosolic cGAS-stimulator of interferon genes (STING) signaling, and inflammasome activation, which then mediate downstream inflammatory cascades. In this review, we summarize the characteristics of these mtDNA-sensing pathways mediating inflammatory responses and their role in the pathogenesis of acute kidney injury, nondiabetic chronic kidney disease, and diabetic kidney disease. In addition, we highlight targeting of mtDNA-mediated inflammatory pathways as a novel therapeutic target for these kidney diseases.
Highlights
Mitochondria are double membrane-bound organelles that appear in most eukaryotic cells
When the mitochondria are injured, a variety of mitochondrial components will be released into the cytoplasm or extracellular environment and recognized as damage-associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs), promoting downstream proinflammatory responses [3, 4]
Many other mitochondrial components such as N-formyl peptides, adenosine triphosphate (ATP), and cardiolipin can act as mitochondrial DAMPs, we focus on mitochondrial DNA in this review
Summary
Mitochondria are double membrane-bound organelles that appear in most eukaryotic cells. TFAM deficiency causes mtDNA mispackaging and leaking into the cytosol resulting in the activation of cGAS-STING pathway and the upregulation of downstream NF-κB which underlies the renal fibrosis and inflammation in CKD progression [93]. Mitochondrial dysfunction and the subsequent NLRP3 inflammasome activation have been linked to renal tubular injury and tubulointerstitial fibrosis in albumin-overload mouse models and aldosterone-treated human tubular epithelial cells [95, 96]. Note: 5-HT1F, 5-hydroxytryptamine 1F; AKI, acute kidney injury; CKD, chronic kidney disease; CLP, cecal ligation and puncture; i.p., intraperitoneal; i.v., intravenous; IRI, ischemia/reperfusion injury; MB, mitochondrial biogenesis; mPTC, mouse proximal tubular cells; mPTP, mitochondrial permeability transition pore; MTD, mitochondrial debris; mtDNA, mitochondrial DNA; RTEC, renal tubular epithelial cells; STING, stimulator of interferon; TLR9, Toll-like receptor 9. These results indicate that mtDNA change in mesangial cells may contribute to the development of DKD
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