# Mechanism of Mitochondrial Dysfunction in COPD

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $385,000

## Abstract

SUMMARY
Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of chronic morbidity and mortality,
both in the United States (affecting an estimated 23 million people) and globally. Cigarette smoke (CS), the
most important etiological risk factor for the development of COPD/emphysema, causes lung injurious and
damaging responses. These effects include mitochondrial dysfunction (i.e., reduced mitochondrial membrane
potential and increased mitochondrial reactive oxygen species [mtROS] generation), and defective mitophagy
(removal of damaged mitochondria from a cell prior to cell death). Our preliminary data show that CS-induced
defective mitophagy is associated with perinuclear localization of dysfunctional mitochondria and disruption of
telomere-shelterin complex (a complex which protects telomeres from DNA damage) in lung cells. We further
show that the transfer of mitochondria occurs from mesenchymal stem cells (MSCs) into senesced lung
epithelial cells, and protects against CS-induced senescence-associated secretory phenotype and
mitochondrial dysfunction in vitro and in vivo. However, the cellular and molecular mechanisms for CS-induced
mitophagy impairment and shelterin complex mitochondrial translocation, as well as their roles in cellular
senescence during the development of COPD/emphysema are not known. We hypothesize that CS-induced
mitochondrial dysfunction leads to defective mitophagy by disrupting the protective shelterin telomere capping
protein complex, and that healthy mitochondrial transfer into damaged lung epithelial cells protects against CS-
induced injurious responses in COPD/emphysema. To test these hypotheses, we will pursue the following
three Specific Aims in this 4-year R01.
(1) Determine the molecular mechanisms underlying CS-induced mitochondrial dysfunction and defective
mitophagy.
(2) Determine the mechanism of disrupted shelterin complex in CS-induced mitochondrial dysfunction and
impaired mitophagy.
(3) Determine the protective and/or restorative influence of Miro1 (mitochondrial Rho-GTPase)-dependent
fresh/healthy mitochondrial transfer during CS-induced pulmonary emphysema.
The outcome of this proposal will unravel novel molecular mechanisms for CS-induced mitochondrial
dysfunction, shelterin complex disruption, and senescence in lung injurious and damaging responses during
the pathogenesis of COPD/emphysema. The proposed studies have considerable translational potential as
they will determine the mechanisms whereby possible attenuation of the telomere shelterin complex and/or
Miro1-mediated mitochondria transfer can be utilized as novel therapeutic targets for the
treatment/management of COPD/emphysema.

## Key facts

- **NIH application ID:** 9982403
- **Project number:** 5R01HL137738-04
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** IRFAN RAHMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982403

## Citation

> US National Institutes of Health, RePORTER application 9982403, Mechanism of Mitochondrial Dysfunction in COPD (5R01HL137738-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9982403. Licensed CC0.

---

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