Disordered mitochondrial proteostasis and alveolar epithelial repair in the aging lung

About This Grant

PROJECT SUMMARY Pneumonia, the most common cause of death from an infectious disease worldwide, disproportionately affects the elderly. This disproportionate impact of pneumonia in older individuals became evident to all during the COVID-19 pandemic, which caused the death of nearly 7 million mostly elderly people worldwide. Furthermore, older pneumonia survivors are at increased risk for age-related disorders including persistent lung injury, skeletal muscle dysfunction leading to immobility, cognitive impairment, and dementia, highlighting pneumonia as a gateway for the compounding morbidity that limits healthspan at the end of life. We published a mechanistic model to explain the worsened lung injury and impaired lung recovery after viral pneumonia in old compared with young mice and humans. Respiratory viruses infect alveolar epithelial cells damaging the alveolar membrane. The loss of alveolar epithelial cells activates a process of repair, which is primarily mediated by alveolar epithelial type 2 (AT2) cells, the major progenitor cell population in the alveolus. AT2 cells proliferate and differentiate into alveolar epithelial type 1 (AT1) cells to restore the alveolar epithelium. Using single-cell RNA-sequencing, we and others identified a “transitional epithelial cell” population that accumulates during AT2 to AT1 differentiation. During postnatal development, we causally linked an increase in the NADH/NAD+ ratio resulting from dysfunction in complex I of the mitochondrial electron transport chain to pathologic activation of the integrated stress response (ISR) that led to the accumulation of transitional cells and death of the animal during alveologenesis. Our preliminary data reveal that loss of mitochondrial complex I function in AT2 cells of young adult mice leads to progressive fatal lung fibrosis. These findings support our hypothesis that age-related dysfunction in complex I of the mitochondrial electron transport chain increases NADH/NAD+ to induce pathologic activation of the ISR that acts via ATF4 and ATF5 to prevent alveolar epithelial repair after viral pneumonia. We will test this hypothesis in three interrelated Specific Aims. Aim 1: To determine whether age-related changes in mitochondrial complex I function or the mitochondrial NADH/NAD+ ratio in alveolar epithelial cells is necessary for the failure of alveolar epithelial repair after viral pneumonia. Aim 2. To determine whether activation of the ISR is necessary for alveolar epithelial repair after viral pneumonia. Aim 3: To determine whether activation of ATF4 alone or in combination with ATF5 in AT2 cells is necessary for the age-related failure of alveolar epithelial repair after viral pneumonia. Completion of these Aims will credential therapies targeting the NADH/NAD+, ISR, ATF4, and ATF5 to reduce the morbidity and mortality associated with viral pneumonia in the elderly.