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Mitochondrial pyruvate carriers control airway basal progenitor cell function through glycolytic-epigenetic
Yawen Li1, Yalin He1, Qi Zheng2
1Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
Cell Stem Cell
|October 19, 2024
Summary
Mitochondrial pyruvate carriers (MPCs) are crucial for tracheal basal cell (BC) fate. Inhibiting MPCs allows BC expansion and suggests targeting pyruvate-citrate metabolism may treat lung diseases.
Area of Science:
- Cell Biology
- Metabolic Regulation
- Respiratory Medicine
Background:
- Basal cells (BCs) maintain tracheal epithelium integrity.
- BC fate decisions are critical for airway health and regeneration.
- Dysfunctional BCs contribute to lung diseases like COPD.
Purpose of the Study:
- To investigate the role of mitochondrial pyruvate carriers (MPCs) in basal cell (BC) fate.
- To explore the metabolic-epigenetic links governing BC differentiation.
- To identify potential therapeutic targets for lung diseases involving BC dysfunction.
Main Methods:
- Inhibition of mitochondrial pyruvate carriers (MPCs) in mouse and human BCs.
- Genetic inactivation of Mpc2 in mice to study homeostasis and injury response.
- Analysis of metabolic pathways, including glycolysis and acetyl-CoA generation.
- Assessment of epigenetic modifications and gene transcription related to BC differentiation.
- Evaluation of the impact of modulating the pyruvate-citrate axis on BC behavior.
Main Results:
- Mitochondrial pyruvate carriers (MPCs) function as essential metabolic checkpoints for BC fate.
- MPC inhibition enables long-term expansion of both mouse and human BCs.
- Mpc2 inactivation in mice causes BC hyperplasia, impaired regeneration, and accumulation of intermediate cells.
- MPC2 links glycolysis to ACLY-dependent acetyl-CoA production, crucial for epigenetic control of differentiation.
- Targeting the metabolic-epigenetic axis partially rescues YAP-dysfunction phenotypes in BCs.
- Exogenous citrate promotes differentiation of BCs from COPD patients.
Conclusions:
- Pyruvate metabolism, regulated by MPCs, is vital for basal cell (BC) fate decisions.
- The metabolic-epigenetic axis involving MPC2, ACLY, and acetyl-CoA is key for BC differentiation.
- Targeting pyruvate-citrate metabolism offers a potential therapeutic strategy for correcting abnormal BC behavior in lung diseases.
Keywords:
airwaycell fate decisioninjury repairlung basal progenitor celllung epithelium homeostasislung progenitor cell metabolismmitochondrial pyruvate carrierMore Related Videos
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