Kidney mitochondrial DNA as a mediator of IL-6 release during sepsis
OA Version
Citation
Abstract
Sepsis, a global health crisis, is driven by systemic inflammation and organ dysfunction, with the kidney playing a pivotal role due to its susceptibility to mitochondrial damage. This study investigates the role of mitochondrial DNA (mtDNA) in sepsis using next-generation sequencing to develop novel methods of extracellular mtDNA quantification in the cecal ligation and puncture mouse model. We hypothesize that mtDNA, released from the kidney as a damage-associated molecular pattern, contributes to sepsis-induced inflammation by activating systemic cytokine release via toll-like receptor 9 (TLR-9). We found that mtDNA concentrations correlated with systemic cytokine release after sepsis and that kidney mtDNA contributes to IL-6 release via TLR-9 in vitro and in vivo. Additionally, unbiased metabolic profiling revealed increased mitochondrial dysfunction in the kidney compared to other organs, with significant disruptions in fatty acid oxidation and phospholipid metabolism. Finally, we analyzed mtDNA single-nucleotide polymorphism patterns (SNPs) across tissues to identify the primary source of circulating mtDNA. The kidney exhibited the highest total and unique plasma-matching SNPs, establishing it as an important contributor to circulating cell-free mtDNA during sepsis. These findings position kidney-derived mtDNA as a key driver of systemic inflammation in sepsis, providing a rationale for kidney mitochondrial health and mtDNA as therapeutic targets in sepsis.
Description
2025