# Elucidating the contribution of mitochondrial calcium uptake to lung epithelial regeneration

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2024 · $702,675

## Abstract

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.

## Key facts

- **NIH application ID:** 10853935
- **Project number:** 1R01HL172848-01
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Ying Tian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $702,675
- **Award type:** 1
- **Project period:** 2024-06-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10853935

## Citation

> US National Institutes of Health, RePORTER application 10853935, Elucidating the contribution of mitochondrial calcium uptake to lung epithelial regeneration (1R01HL172848-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10853935. Licensed CC0.

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