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This research investigates the role of mitochondrial DNA in immune activation after cardiac arrest and its implications for treatment.

January 10, 2026Journal of the American Heart Association0 citationsOpen Access

Mitochondrial DNA‐Mediated Immune Activation After Resuscitation From Cardiac Arrest

TRTyler RollandUniversity at Buffalo, State University of New York EHEmily R. HudsonVA Western New York Healthcare System LGLuke GraserUniversity at Buffalo, State University of New York

Key Result

Circulating mitochondrial DNA levels increased by ~250-fold after return of spontaneous circulation, triggering leukocyte activation and inflammation post-cardiac arrest.

Key Points

This research investigates the role of mitochondrial DNA in immune activation after cardiac arrest and its implications for treatment.
Measured plasma mtDNA and nuclear DNA levels in swine and humans after cardiac arrest.
Tested the effects of mtDNA and extracellular vesicles on porcine immune cells in vitro.
Utilized pharmacological agents to inhibit TLR9 and cGAS pathways involved in mtDNA sensing.
Circulating mtDNA increased by approximately 250-fold after cardiac arrest, while nuclear DNA levels remained stable.
mtDNA was primarily released in extracellular vesicles, indicating a conserved release mechanism across species.
Internalization of mtDNA-containing extracellular vesicles was crucial for activating leukocytes, with potential therapeutic targets identified.

Structured PICO

Does mitochondrial DNA release trigger leukocyte activation after sudden cardiac arrest, and can targeting TLR9 or cGAS pathways attenuate this inflammation?

Population

Swine subjected to sudden cardiac arrest (n=8) or brief myocardial ischemia (n=5); 57 successfully resuscitated out-of-hospital cardiac arrest (sR-OHCA) human patients (mean age 63.1, 34 male/17 female) from 4 US hospitals, a validation cohort of 32 sR-OHCA patients, and 9 healthy controls; and porcine peripheral blood mononuclear cells.

Intervention

In vitro treatment with mitochondrial DNA (mtDNA) or extracellular vesicles (EVs) isolated from post-ROSC plasma, and pharmacological inhibition of TLR9 (ODN 2088, ODN inh-18) and cGAS (G140) pathways.

Comparator

Healthy human controls, pre-ischemia baseline samples, and unstimulated or vehicle-treated cells.

Outcome

Plasma mtDNA and nuclear DNA levels at ~4 hours post-ROSC, and leukocyte activation (phenotypic shifts toward inflammatory dendritic cells and macrophages, and proinflammatory cytokine secretion).surrogate

Mitochondrial DNA released within extracellular vesicles after cardiac arrest triggers robust leukocyte activation, suggesting TLR9 and cGAS pathways are promising targets to reduce sterile inflammation in postcardiac arrest syndrome.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

Background Postcardiac arrest syndrome is characterized by systemic inflammation that contributes to poor outcomes after resuscitation from sudden cardiac arrest. Mitochondrial DNA (mtDNA) has been implicated as a proinflammatory stimulus in other contexts, but its role in postcardiac arrest syndrome is unclear. We determined if postcardiac arrest syndrome is characterized by a rise in circulating mtDNA, how mtDNA activates immune cells, and if targeting mtDNA‐sensing pathways attenuates leukocyte activation. Methods Plasma mtDNA and nuclear DNA levels were measured ~4‐hours after return of spontaneous circulation following sudden cardiac arrest in swine (n=8) and humans (n=57). Additionally, porcine peripheral blood mononuclear cells were treated with mtDNA or extracellular vesicles (EVs) isolated from porcine plasma collected after return of spontaneous circulation. Pharmacological agents were used to inhibit TLR9 (toll‐like receptor 9)‐ and cGAS (cyclic GMP–AMP synthase)‐mediated mtDNA sensing. Results A ~250‐fold elevation in circulating mtDNA was observed after return of spontaneous circulation in swine despite negligible changes in circulating nuclear DNA, a finding that was corroborated in humans. Circulating mtDNA was largely encapsulated within EVs in both species, suggesting a conserved mechanism of release. In vitro studies demonstrated that peripheral blood mononuclear cell internalization of mtDNA‐containing‐EVs was required for leukocyte activation. This response was attenuated by EV disruption, DNA degradation, and blockade of TLR9 or cGAS pathways, identifying novel targets to modulate inflammation in postcardiac arrest syndrome. Conclusions Brief whole‐body ischemia and reperfusion in the context of resuscitation from sudden cardiac arrest elicits mtDNA release, primarily within EVs, that triggers leukocyte activation. Targeting mtDNA release or its downstream sensors may offer a new therapeutic strategy to improve outcomes after sudden cardiac arrest.

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