# Mechanisms of Alveolar Mitochondrial Damage and Resolution in Pneumonia

> **NIH VA I01** · DURHAM VA MEDICAL CENTER · 2021 · —

## Abstract

Abstract
 Acute Lung Injury (ALI) afflicts ~200,000 people in the United States every year and >30% of
these patients die. ALI is characterized by severe alveolar inflammation caused primarily by
pneumonia, sepsis, and aspiration, causing loss of alveolar type I epithelial cells and failure of alveolar
barrier function. New treatments for ALI have failed, partly because of the injury heterogeneity and
uncertainty about appropriate drug targets. Delayed resolution of ALI is related to alveolar epithelial
cell (AEC) death; however there is excessive mitochondrial damage in pneumonia/ALI that exceeds
the degree of cell death. We have linked ALI mitigation to genetic mechanisms of mitochondrial
quality control (MQC). MQC eliminates mitochondrial damage from cells by coordinated induction of
mitochondrial biogenesis and mitophagy, regulated by inducible transcription factors, such as nuclear
respiratory factor 1 (NRF-1) and it partner, PGC-1. NRF-1 regulates key genes for mitochondrial
DNA transcription and replication. Mitochondrial DNA (mtDNA) damage disrupts MQC, and escape
of mtDNA from cells is inflammatory and consistent with impaired mitophagy and MQC in ALI.
Mitochondrial function also declines with age, and age correlates with declining lung function and
more severe ALI. Thus, mtDNA release may be a useful biomarker. We propose that pneumonia/ALI
increases mtDNA damage in AECs and impairs MQC activity that lower mitochondrial oxidant
production and inflammasome assembly, promotes AEC cell survival and improves ALI resolution.
These mechanisms will be tested for activation in a second model (hyperoxia) and for waning effect in
aging lung with prolonged long and multiple environmental oxidant exposures and acquired defects
in mtDNA. To test the hypothesis, we propose three Specific Aims:
 Aim 1: To identify mitochondrial DNA oxidation (8-OHdG) in lung AECs with changes in
mitochondria reserve, respiration by Seahorse technology, cell oxidant production by fluorescent
probes, MQC protein induction analysis, and AEC MQC localization and cell death by confocal
microscopy during S. aureus pneumonia/ALI in young adult mice
 Aim 2: To examine loss of mtDNA and mitochondrial reserve and its role in inflammasome
activation, mitophagy and necroptosis in S. aureus pneumonia/ALI in older mice. We will use
mitochondrial catalase (mCAT) mice to protect mtDNA and measure changes in lung inflammasome
assembly and cell death.
 Aim 3: To examine the frequency of mtDNA oxidation and MQC distribution in AECs in
human patients dying of ALI/ARDS compared with healthy age-matched controls. We will use
immunofluorescence distributions and determine relationships of damage to age, oxygen dose, and
ongoing inflammatory response.
 These Aims will support proof-of-principle for MQC recruitment and prevention of mtDNA
oxidation as a critical lung cell defense involved in ALI resolution, determine the impact of lung aging
on MQC and ALI resolution, and lay a molecular bas...

## Key facts

- **NIH application ID:** 10044401
- **Project number:** 5I01BX004289-02
- **Recipient organization:** DURHAM VA MEDICAL CENTER
- **Principal Investigator:** KAREN E WELTY-WOLF
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10044401

## Citation

> US National Institutes of Health, RePORTER application 10044401, Mechanisms of Alveolar Mitochondrial Damage and Resolution in Pneumonia (5I01BX004289-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10044401. Licensed CC0.

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