# Modulating mitochondrial function to promote proteostasis in the aging lung

> **NIH NIH P01** · NORTHWESTERN UNIVERSITY · 2022 · $395,576

## Abstract

PROJECT SUMMARY
Individuals aged 65 years or older account for 80-90% of deaths from influenza A virus each year. The
overarching goal of this project is to systematically test the hypothesis that modulating mitochondrial function
can alter lung repair after influenza A infection. In the first cycle, we generated data in the C. elegans model to
suggest that the mild reduction in mitochondrial electron transport capacity during aging promotes proteostasis.
To test this hypothesis in a mammalian system, we began to age Ndufs2 heterozygous (Ndufs2+/-) mice. Ndufs2
is a catalytic subunit of complex I of the mitochondrial electron transport chain. Ndufs2 heterozygous mice have
a 50% reduction in maximal mitochondrial complex I capacity, but appear normal up to one year of age. In
contrast, our preliminary data indicate that complete loss of Ndufs2 in alveolar epithelial cells causes the death
of mice at a young age. Interestingly, loss of an accessory subunit of mitochondrial complex I, Ndufs4, which
results in ~80% loss of mitochondrial complex I function (hypomorph), does not cause lung pathology at baseline.
This has led us to hypothesize that mild reductions in mitochondrial complex I function will improve recovery
after influenza A infection, while more severe reductions will induce high levels of ATF4 that will impair lung
repair. Our preliminary data also indicate that regulatory T cells (Tregs) are essential for alveolar epithelial cell
repair after influenza A virus infection. Tregs from aged mice have increased DNA hypermethylation and are
unable to repair influenza A virus-induced lung injury. Thus, we will determine whether partial or complete loss
of mitochondrial complex I function in Tregs prevents lung repair after influenza A virus infection. Collectively
these hypotheses will be tested in three interrelated Specific Aims: (1) Does a decline in maximal mitochondrial
complex I function (Ndufs2+/- mice) over a lifespan improve recovery from influenza A-induced pneumonia during
aging? (2) Is ATF4 activation required for the increase in influenza A-induced lung injury induced by the complete
loss or hypomorph of mitochondrial complex I function in alveolar epithelial cells? (3) Is the complete loss or
hypomorph of mitochondrial complex I function in regulatory T cells (Tregs) sufficient to dampen their ability to
promote tissue repair after lung injury?

## Key facts

- **NIH application ID:** 10417060
- **Project number:** 5P01AG049665-08
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** NAVDEEP S CHANDEL
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $395,576
- **Award type:** 5
- **Project period:** 2015-07-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10417060

## Citation

> US National Institutes of Health, RePORTER application 10417060, Modulating mitochondrial function to promote proteostasis in the aging lung (5P01AG049665-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10417060. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*