# Metabolic dysfunction regulates mitophagy-dependent necroptosis in COPD

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $553,373

## Abstract

PROJECT SUMMARY
The mechanisms underlying the pathogenesis of chronic obstructive pulmonary disease (COPD), primarily
associated with cigarette smoking (CS), including emphysema and bronchitis, remain unclear. Our published
studies have suggested that autophagy, a lysosome-dependent pathway for the degradation of organelles and
proteins, represents a major cellular and tissue response to CS exposure, in both experimental and human
COPD lung. Emerging studies suggest that autophagy, while well established as a cellular survival process, can
exert homeostatic or detrimental effects in complex diseases. Our studies were the first to demonstrate
deleterious effects of autophagy and mitochondrial autophagy (mitophagy) in experimental models of COPD.
Mice genetically deficient in the mitophagy regulator PINK1 were resistant to experimental COPD. We
discovered that mitophagy induced by CS in response to mitochondrial dysfunction activates programmed
epithelial cell death, in particular the necroptosis mode of cell death. Our Preliminary Studies indicate that CS
exposure can disrupt metabolic pathways, including dysregulation of oxidative phosphorylation (OXPHOS) and
inhibition of fatty acid (FA) synthesis. Hence, we put forth the following Hypothesis: CS exposure causes
epithelial cell metabolic disruption and impaired FA synthesis that causes mitochondrial dysfunction, leading to
activation of PINK1-dependent mitophagy. Mitophagy in turn drives a pro-pathogenic mechanism dependent on
the activation of necroptosis. Activation of this mitophagy-dependent necroptosis pathway in response to
metabolic and mitochondrial dysfunction may adversely affect airway function and emphysema outcomes during
CS-induced COPD pathogenesis. To test this hypothesis, we will address three Specific Aims: Specific Aim 1:
To determine the mechanisms by which CS induces mitophagy in the lung. Specific Aim 2: To determine the
effect of impaired OXPHOS and FA synthesis on the regulation of mitochondrial dynamics and biogenesis and
their impact on experimental COPD. Specific Aim 3: To determine the regulation of cellular necroptosis by CS,
and its impact on lung functional impairment in experimental models of COPD.

## Key facts

- **NIH application ID:** 9850124
- **Project number:** 5R01HL132198-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** MARY E CHOI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $553,373
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850124

## Citation

> US National Institutes of Health, RePORTER application 9850124, Metabolic dysfunction regulates mitophagy-dependent necroptosis in COPD (5R01HL132198-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9850124. Licensed CC0.

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