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Loss of the Mitochondrial Regulator TFAM in Alveolar Epithelial Cells Drives Lung Fibrosis [whole lung]

ABSTRACT: Mitochondrial dysfunction in alveolar epithelial cells is implicated in idiopathic pulmonary fibrosis (IPF), but the upstream epithelial drivers remain unclear. This study tests whether loss of TFAM, a key regulator of mitochondrial DNA maintenance and oxidative phosphorylation, is sufficient to reprogram alveolar type 2 (AT2) cells and promote pro-fibrotic gene programs. We generated bulk RNA-seq datasets from (i) primary mouse AT2 cells following ex vivo Cre-mediated Tfam deletion versus matched controls and (ii) whole-lung tissue from mice with AT2-specific Tfam loss versus controls. These data enable analysis of TFAM-dependent epithelial stress and state-transition signatures and associated remodeling pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE315898 | GEO | 2026/09/22

REPOSITORIES: GEO

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Loss of the Mitochondrial Regulator TFAM in Alveolar Epithelial Cells Drives Lung Fibrosis [in vitro]

Project description:Mitochondrial dysfunction in alveolar epithelial cells is implicated in idiopathic pulmonary fibrosis (IPF), but the upstream epithelial drivers remain unclear. This study tests whether loss of TFAM, a key regulator of mitochondrial DNA maintenance and oxidative phosphorylation, is sufficient to reprogram alveolar type 2 (AT2) cells and promote pro-fibrotic gene programs. We generated bulk RNA-seq datasets from (i) primary mouse AT2 cells following ex vivo Cre-mediated Tfam deletion versus matched controls and (ii) whole-lung tissue from mice with AT2-specific Tfam loss versus controls. These data enable analysis of TFAM-dependent epithelial stress and state-transition signatures and associated remodeling pathways.

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Mitochondrial transcription factor A (TFAM) represses the expression of interferon signaling genes in human lung epithelial cells

Project description:Mitochondrial transcription factor A (TFAM) is associated with a number of neurodegenerative diseases and also with asthma. TFAM deficiency-induced mitochondrial DNA stress primes the antiviral innate immune response in mouse embryonic fibroblasts. In this study, we overexpressed TFAM in human lung epithelial cells (A549), then obtained and analyzed the TFAM-regulated transcriptome by Illumina-sequencing technology. We found that TFAM overexpression down-regulated and up-regulated the expression 642 and 169 genes (DEGs), respectively. The TFAM-repressed genes were highly enriched in cytokine-mediated signaling pathway, type I interferon- and INFmediated signaling pathways, and viral response pathways. We also revealed that 2563 alternative splicing events in 1796 genes (ASG) were de-regulated upon TFAM overexpression. These TFAM-responding ASGs were strongly enriched in DNA repair, nerve growth factor receptor signaling pathway, and also transcription regulation. Further analysis revealed that the promoters of TFAM-repressed DEGs were enriched by DNA binding motifs of transcription factors whose alternative splicing regulated by TFAM. These findings suggested that TFAM regulates not only immune response gene expression in human lung epithelial cells, but also alternative splicing which may play a role in mediating transcriptional regulation. This TFAM-centered gene regulation network could be targeted in developing therapies against various diseases.

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