Basal cells (BCs) are stem cells responsible for maintaining tracheal epithelial integrity. Dysregulation of basal cell function is associated with the pathogenesis of various lung diseases, such as chronic obstructive pulmonary disease (COPD), in which the airway epithelium exhibits basal cell hyperplasia, a reduction in ciliated cells, and an increase in premature epithelial cells. Clinical data show that epithelial cells derived from COPD patients exhibit altered mitochondrial structures. These observations suggest that mitochondrial metabolism is linked to basal cell function. However, the underlying mechanisms remain unclear.
In a study published in Cell Stem Cell, researchers led by Prof. SUI Pengfei from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences, in collaboration with Prof. REN Tao from Shanghai Sixth People’s Hospital, reported that mitochondrial pyruvate carriers control airway basal progenitor cell function through glycolytic-epigenetic reprogramming.
Through transcriptomic and metabolic analyses, the researchers found that airway basal cell differentiation correlates with cellular metabolic rewiring, characterized by increased pyruvate uptake and oxidation. Inhibition of mitochondrial pyruvate carriers (MPCs) represses BCs differentiation and enables long-term BCs expansion.
The study demonstrated that the loss of MPCs leads to reduced epithelial turnover and altered cell composition under steady-state conditions. Following injury, mutant mice exhibited defective regeneration of the airway epithelium, accompanied by an increase in immature luminal cells. These data highlight the importance of mitochondrial pyruvate metabolism in controlling basal cell function.
The researchers further found that the loss of MPCs results in reduced citrate abundance, leading to diminished cytosolic acetyl-CoA generation and insufficient histone acetylation.
Inhibition of histone deacetylation or supplementation of citrate rescued the defective cell differentiation phenotype induced by MPC inhibition, thereby establishing a metabolic-epigenetic regulatory axis that directs BC fate decisions.
Moreover, the researchers proposed that modulating pyruvate-citrate metabolism can correct abnormal basal cell behavior. Inhibition of MPCs prevents YAP deletion-induced basal cell loss, while citrate supplementation can partially rescue the defective differentiation of BCs with forced activation of YAP. Importantly, exogenous citrate promoted the differentiation of BCs from COPD patients. These data thus identify the therapeutic vulnerability of BC-related lung diseases.
In summary, this study reveals the role of mitochondrial pyruvate metabolism in regulating basal cell fate decisions and suggests that targeting cellular metabolism could be a potential therapeutic avenue for treating basal cell-related human diseases.
Reference: https://doi.org/10.1016/j.stem.2024.09.015
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