# Mitochondrial quality control and alveolar damage resolution after acute lung injury

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $397,500

## Abstract

This application defines the mitochondrial quality control (QC) network in the lung as a
therapeutic target during acute lung injury (ALI/acute respiratory distress syndrome; ARDS), a
major critical illness caused by injury to the alveolar-capillary barrier. The proposal is based on
recent developments from our laboratory on the role of mitochondria in the mechanisms of ALI
resolution. ALI is caused by severe damage to the alveolar-capillary barrier, leading to an
exudative phase of protein-rich edema and cellular debris resulting in physiological shunt and
refractory hypoxemia. Severity is such that the abundant cuboidal alveolar type II (AT2) cell, the
source of surfactant production/recycling, is also thought to be necessary to regenerate type I
cell epithelium and restore epithelial integrity. Accordingly, if the proliferative phase is controlled,
the resolution of alveolar barrier integrity and liquid clearance gradually occurs. The AT2 cell
also supports various non-surfactant alveolar functions from sodium transport to host defense
that require ATP, and hence are enriched in mitochondria. These mitochondria are maintained
by a sentinel genetic mitochondrial QC network, which is also required for cell proliferation and
possibly for alveolar regeneration. Our preliminary data shows that the transcriptional program
that regulates the mitochondrial QC network becomes highly activated in the lung AT2 cell
during experimental Staphylococcal aureus pneumonia/ALI in mice. The resolution of ALI
depends on the inducible heme oxygenase-1 (HO-1; Hmox1) system in the AT2 cell and is
regulated by and regulates antioxidant response element (ARE)-dependent genes. Specifically,
the DNA-binding transcription factor NRF-1 (Nuclear Respiratory Factor-1), a partner of the
PGC-1 co-activator, is critical not only to maintain bioenergetic function, but for the AT2 cell to
serve as an AT1 cell progenitor. We propose that the AT2 cell mitochondrial QC program is
necessary for AT1 proliferation and the full resolution of alveolar epithelial damage in ALI. This
idea is not just novel; it is amenable to therapeutic intervention. Thus, targeted pharmacological
interventions may shorten the course of ARDS. Therefore, using molecular methods with a pre-
clinical approach in mice and cells, we will rigorously test transcriptional activation of
mitochondrial QC in the AT2 cell as a critical factor in ALI resolution through enablement of AT2
cell proliferation, trans-differentiation into AT1 cells, and control of inflammation, all of which are
necessary to restore epithelial barrier function. We will test our novel ideas with three Specific
Aims: Aim 1) Measure and localize oxidant damage in lung parenchyma and AT2 cell
mitochondria (specifically mtDNA oxidation) in ALI/pneumonia in mice and its impact on
mitochondrial QC regulation by HO-1/CO and a) AT2 cell apoptosis, b) resolution of alveolar
inflammation and c) alveolar barrier dysfunction. Aim 2) Test how HO-1 induct...

## Key facts

- **NIH application ID:** 9936405
- **Project number:** 5R01HL135239-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** KAREN E WELTY-WOLF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,500
- **Award type:** 5
- **Project period:** 2017-08-10 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936405

## Citation

> US National Institutes of Health, RePORTER application 9936405, Mitochondrial quality control and alveolar damage resolution after acute lung injury (5R01HL135239-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9936405. Licensed CC0.

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