# mtDNA damage and DAMPs in multiple organ dysfunction syndrome

> **NIH NIH R01** · UNIVERSITY OF SOUTH ALABAMA · 2021 · $438,552

## Abstract

Management of severely injured patients is challenging because Multiple Organ Dysfunction Syndrome may
advance relentlessly even if the initial insult is controlled. However, a series of reports point to the prospect
that mitochondrial (mt)-associated pathways play a central role. Specifically, it has been discovered that
oxidative mtDNA damage is both cytotoxic and leads to its fragmentation into proinflammatory mtDNA Damage
Associated Molecular Patterns with the potential to disseminate injury to distant organs. Against this
background, the goal of this project is to provide insight into the origin, characteristics, and biological
effects of mtDNA DAMPs in the setting of trauma-related MODS as a prelude for translating mtDNA-
directed therapies into clinical application. We will use a clinically-relevant porcine model of MODS induced
by hemorrhage with truncal ischemia and reperfusion to address three Aims. Because conventional strategies
for analysis of circulating mtDNA DAMPs use PCR to quantify sequences of about 200 bp in length, it is likely
that the most prevalent or biologically relevant mtDNA DAMP species have not been identified. In addition,
there are tissue-specific differences in mtDNA sequences that may dictate sequence characteristics of
circulating mtDNA DAMPs. Accordingly, Aim 1 will define sequence characteristics of mtDNA DAMPs released
during the evolution of trauma-related MODS and test the hypothesis that unique variant signatures of
circulating mtDNA can be traced to specific organs and that fail. The second aim addresses the origin of
mtDNA fragments accumulating in the circulation after trauma. In this regard, it has been known for decades
that interuption of mesenteric lymphatic drainage forestalls MODS, thus supporting the concept that the liver-
gut-mesenteric axis could be a major source of circulating mtDNA DAMPs, perhaps stimulating mtDNA DAMP
production in other organs. Aim 2 will therefore test the hypotheses that in trauma, mtDNA DAMPs are
present in the mesenteric lymphatic drainage and that an intact mesenteric lymphatic drainage system is
required for systemic mtDNA DAMP accumulation and MODS. Finally, prevention or reversal of mtDNA
damage with novel fusion protein constructs targeting DNA repair enzymes to mitochondria and
pharmacological enhancement of mtDNA DAMP degradation with a repurposed agent, DNase1, forestalls IR
injury in rodents. Importantly, however, neither of these strategies have been explored in a clinically-relevant
animal model. As a consequence, critical mechanistic insight, particularly the purported operation of a feed-
forward pathway linking mtDNA damage to mtDNA DAMP production, is unavailable. Accordingly, to provide
information needed for translation of mtDNA-directed therapies into clinical application, Aim 3 will use test the
hypothesis that mt-targeted Ogg1 and DNase1, given alone or in combination, alter disposition of circulating
mtDNA DAMPs and suppress MODS.

## Key facts

- **NIH application ID:** 10092191
- **Project number:** 5R01GM127823-03
- **Recipient organization:** UNIVERSITY OF SOUTH ALABAMA
- **Principal Investigator:** MARK N GILLESPIE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $438,552
- **Award type:** 5
- **Project period:** 2019-05-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092191

## Citation

> US National Institutes of Health, RePORTER application 10092191, mtDNA damage and DAMPs in multiple organ dysfunction syndrome (5R01GM127823-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10092191. Licensed CC0.

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