Kidney mitochondrial DNA contributes to systemic IL-6 release in sepsis-associated acute kidney injury.

Summary

Using CLP mice, NGS and droplet digital PCR pinpointed kidney-origin mtDNA as elevated in plasma post-sepsis and mechanistically linked to IL-6 release via TLR9. Kidney mitochondrial preparations increased IL-6 in vivo; TLR9 inhibition mitigated IL-6. In patients, plasma mtDNA was higher in septic AKI and correlated with IL-6.

Key Findings

• Plasma mtDNA increased after CLP versus shams; SNP profiling indicated kidney origin predominance.
• Kidney mtDNA triggered IL-6 and mtDNA release from dendritic cells; kidney mitochondrial solution elevated IL-6 in vivo.
• TLR9 inhibition reduced IL-6 release; in patients, plasma mtDNA was higher with septic AKI and correlated with IL-6.

Clinical Implications

Supports development of mtDNA/TLR9-targeted strategies and validates plasma mtDNA as a potential biomarker to stratify risk and monitor S-AKI inflammation.

Limitations

• Preclinical CLP model and observational human data limit causal inference for clinical outcomes
• TLR9 inhibition not evaluated in clinical trials; sample sizes not detailed in abstract

Future Directions

Prospective human studies testing TLR9 antagonists or mtDNA-lowering strategies in S-AKI; validation of plasma mtDNA as a prognostic/theragnostic biomarker.