Aging-associated transcriptional programming of mitochondrial respiration in alveolar type II epithelial cells

Alveolar type II epithelial cells (AT2), notable for their high mitochondria content, are essential for maintaining pulmonary homeostasis. However, how mitochondrial function was transcriptionally programmed during AT2 aging remains poorly understood. Here, we used single-cell transcriptome data from 28 healthy human lungs spanning various ages to systematically profile age-related transcriptional changes. Our data suggest that most classical aging markers remained stable with no significant changes during AT2 aging. Using high-dimensional weighted gene co-expression network analysis (hdWGCNA), we identified a gene expression module (M1) that declines during AT2 aging and is enriched for genes involved in mitochondrial respiration. Moreover, by integrating bioinformatic and experimental approaches, we found three transcription factors (TCF7L2, FOXJ3, and TCF7) that play key regulatory roles in controlling expression of mitochondrial respiration-related genes during AT2 aging. Collectively, our findings provide both a transcriptional framework and candidate mitochondria regulators to facilitate future investigation of the causal links between AT2 mitochondrial respiration dysfunction and age-related decline in lung function.