Sunday, May 18, 2025
5/18/2025
Elucidating the contribution of mitochondrial calcium uptake to lung epithelial regeneration - SUMMARY This project aims to investigate the factors involved in lung epithelial regeneration following bacterial pneumonia. The regeneration process relies on the activity of stem/progenitor cells, particularly lung alveolar epithelial type 2 (AT2) cells, which differentiate into alveolar epithelial type 1 (AT1) cells. However, defects in this differentiation process occur in certain populations, such as the elderly and those with chronic respiratory diseases. Understanding the molecular mechanisms governing AT2 cell activity is crucial for developing effective therapeutic approaches. This project is based on the hypothesis that calcium-dependent metabolic changes drive epigenetic reprogramming, promoting the gene program required for AT2-to-AT1 cell differentiation. Specifically, the lysine trimethylation status of histone H3, controlled by Jumonji C (JmjC) domain-containing histone lysine demethylases (JMJDs), plays a key role in regulating gene expression and cellular differentiation. Pharmacological inhibition of JMJDs increased levels of trimethylated histone lysine marks and decreased AT2-to-AT1 cell differentiation, suggesting the necessity of histone lysine demethylation for AT2-to-AT1 cell differentiation. The activity of JMJDs is regulated by the succinate/α-ketoglutarate (αKG) ratio, which is influenced by mitochondrial matrix Ca2+ (mCa2+) levels. MICU1, a regulatory subunit of the mitochondrial Ca2+ uniporter channel, controls mCa2+ uptake from the cytoplasm into mitochondria and affects the succinate/αKG ratio. Our preliminary studies demonstrate that Micu1 deletion in AT2 cells decreased glutaminolysis feeding into the TCA cycle, increased succinate/αKG ratio and levels of histone lysine trimethylation marks. Additionally, supplementation with succinate increased histone lysine trimethylation marks and inhibited AT2-to-AT1 cell differentiation. Based on these findings, we propose that MICU1- dependent mCa2+ uptake regulates AT2 cell differentiation capacity by controlling the succinate/αKG ratio. This reinforcement of αKG-dependent JMJD activity promotes the gene program required for AT2-to-AT1 cell differentiation. This project has three specific aims. In aim 1, we will investigate how the succinate/αKG ratio connects MICU1-dependent mCa2+ uptake to AT1 cell fate during AT2-to-AT1 cell differentiation. Aim 2 will determine the mechanistic role of glutaminolysis in AT2-to-AT1 cell differentiation and lung epithelial repair. In aim 3, we will determine whether histone lysine trimethylation marks, regulated by MICU1-dependent mCa2+ uptake, control the gene program necessary for AT2-to-AT1 cell differentiation. Through unique mutant mouse models and clinically-relevant model systems, this project will provide valuable insights into the mechanisms underlying lung epithelial regeneration and contribute to the development of novel therapeutic strategies for bacterial pneumonia-induced injury.
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