# The Role of Mitochondrial DNA in Innate Immune Activation after Sudden CardiacArrest

> **NIH VA IK2** · LOUIS STOKES CLEVELAND VA MEDICAL CENTER · 2024 · —

## Abstract

ABSTRACT
Sudden cardiac arrest is highly prevalent among hospitalized veterans and results in overwhelming mortality.
Unfortunately, there are no pharmacologic therapies that have been shown to reliably increase survival after
sudden cardiac arrest. Survivors of sudden cardiac arrest typically have systemic organ damage requiring
intensive care in the hospital. The majority of these patients have reduced cardiac function and one quarter of
these patients die from cardiogenic shock. Cardiac inflammation is thought to contribute to this dysfunction and
is likely driven by damage associated molecular patterns (DAMPs). One prominent DAMP is mitochondrial
DNA (mtDNA). Preliminary work in our lab has shown that strategies aimed at preserving mtDNA integrity,
including overexpression of mitochondrial transcription factor A (TFAM), are protective to cardiac function in a
mouse model of sudden cardiac arrest. TFAM is a nuclear gene that regulates mtDNA expression, packaging,
and copy number and is known to be protective in a number of heart disease models.
My overarching hypothesis is that ischemia-reperfusion injury from cardiac arrest results in mtDNA release,
which triggers an inflammatory response in the heart, and that this response is dependent upon cGAS/STING
signaling. To explore this hypothesis, I will pursue three specific aims. In Aim 1, I will explore the mechanism
by which mtDNA is released using microscopy in vitro and confirm these changes in an in vivo model of
sudden cardiac arrest. In Aim 2, I will use transgenic mouse models to manipulate TFAM to affect mtDNA
release and also knock-out STING signaling to explore the relationship between mtDNA release and
inflammation after sudden cardiac arrest. In Aim 3, I will characterize the inflammatory response in the heart
after sudden cardiac arrest and manipulate cGAS/STING signaling to evaluate cGAS/STING mediated
inflammatory changes.
Together, these aims will evaluate the role of mtDNA release following sudden cardiac arrest and its role in
innate immune signaling, which may guide future therapies for human studies. This work will support my goal
of transitioning into an independent research career as a physician-scientist studying mitochondrial changes in
cardiovascular disease. This grant will support continued research and career development at both the
Veterans Administration Hospital in Pittsburgh and the University of Pittsburgh, including coursework, career
mentorship, and scientific training aimed at transitioning to independence as a physician scientist in the
Veterans Administration system.

## Key facts

- **NIH application ID:** 10911024
- **Project number:** 5IK2BX005785-04
- **Recipient organization:** LOUIS STOKES CLEVELAND VA MEDICAL CENTER
- **Principal Investigator:** Cody Andrew Rutledge
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10911024

## Citation

> US National Institutes of Health, RePORTER application 10911024, The Role of Mitochondrial DNA in Innate Immune Activation after Sudden CardiacArrest (5IK2BX005785-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10911024. Licensed CC0.

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