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

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: GSE315897 | GEO | 2026/09/22

REPOSITORIES: GEO

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

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.

2026-09-22 | GSE315898 | GEO

TFAM ChIP-seq in HeLa cells

Project description:ChIP-seq data characterizing the occupancy of TFAM over the mitochondrial and nuclear genomes in HeLa cells. Characterization of mitochondrial and nuclear genome-wide TFAM binding in HeLa cells

2013-09-21 | E-GEOD-48176 | biostudies-arrayexpress

Single Cell RNA-Sequencing Identifies Diverse Roles of Epithelial Cells in Idiopathic Pulmonary Fibrosis

Project description:Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease causing alveolar remodeling, inflammation, and fibrosis. We utilized single cell RNA-sequencing (scRNA-Seq) to identify epithelial cell types and associated biological processes involved in the pathogenesis of IPF. Transcriptomic analysis of epithelial cells from normal human lung defined gene expression patterns associated with highly differentiated alveolar type 2 (AT2) cells, indicated by enrichment of RNAs critical for surfactant homeostasis. In contrast, scRNA-seq of IPF cells identified three distinct subsets of epithelial cell types with characteristics of conducting airway basal and goblet cells and, an additional atypical "transitional" cell that contribute to pathological processes in IPF. Individual IPF cells frequently co-expressed alveolar AT1, AT2, and conducting airway selective markers, demonstrating "indeterminate" states of differentiation not seen in normal lung development. Pathway analysis predicted aberrant activation of canonical signaling via TGF-ß, HIPPO/YAP, P53, and AKT-PI3 Kinase. Immunofluorescence confocal microscopy identified the disruption of alveolar structure and loss of the normal proximal-peripheral differentiation of pulmonary epithelial cells. Single cell transcriptomic analyses of respiratory epithelial cells identified loss of normal epithelial cell identities and unique contributions of epithelial cells to the pathogenesis of IPF. Present scRNA-seq transcriptomic analysis of normal and IPF respiratory epithelial cells provides a rich data source to further explore lung health and disease.

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Single Cell RNA-Sequencing Identifies Diverse Roles of Epithelial Cells in Idiopathic Pulmonary Fibrosis

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Transcriptional responses in TFAM-deficient renal epithelial cells

Project description:Mitochondrial transcription factor A (TFAM) was deleted in renal epithelial cells using the Six2-Cre transgene. To characterize gene expression in TFAM-deficient renal epithelial cells, renal cortices from mutant and Cre-negative control mice were compared.

2021-06-28 | GSE147189 | GEO

Fgf10-Fgfr2b signaling generates basal cells and drives alveolar epithelial regeneration by bronchial epithelial stem cells after lung injury

Project description:Idiopathic pulmonary fibrosis (IPF) is a common form of interstitial lung disease (ILD) resulting in alveolar remodeling and progressive loss of pulmonary function due to chronic alveolar injury and failure to regenerate the respiratory epithelium. Histologically, fibrotic lesions and honeycomb structures expressing atypical proximal airway epithelial markers replace alveolar structures, the latter normally lined by alveolar type 1 (AT1) and AT2 cells. Bronchial epithelial stem cells (BESCs) can give rise to AT2 and AT1 cells or honeycomb cysts following bleomycin-mediated lung injury. However, little is known about what controls this binary decision or whether this decision can be reversed. Here we report that inactivation of Fgfr2b in BESCs impairs their contribution to both alveolar epithelial regeneration and honeycomb cysts after bleomycin injury. By contrast overexpression of Fgf10 in BESCs enhances fibrosis resolution by favoring the more desirable outcome of alveolar epithelial regeneration over the development of pathologic honeycomb cysts.

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Epithelial Yap/Taz are required for functional alveolar regeneration following acute lung injury

Project description:A hallmark of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases is dysregulated repair of the alveolar epithelium. The Hippo pathway effector transcription factors YAP and TAZ are implicated as essential for type 1 and type 2 alveolar epithelial cell (AT1 and AT2) differentiation in the developing lung, yet aberrant activation of YAP/TAZ is a prominent feature of the dysregulated alveolar epithelium in IPF. In these studies, we sought to define the functional role of YAP/TAZ activity during alveolar regeneration. We demonstrated that Yap and Taz are normally activated in AT2 cells shortly after injury, and deletion of Yap/Taz in AT2 cells led to pathologic alveolar remodeling, failure of AT2 to AT1 cell differentiation, increased collagen deposition, exaggerated neutrophilic inflammation, and increased mortality following injury induced by a single dose of bleomycin. Loss of Yap/Taz activity prior to a LPS injury prevented AT1 cell regeneration, led to intra-alveolar collagen deposition, and resulted in persistent innate inflammation. Together these findings established that AT2 cell Yap/Taz activity is essential for functional alveolar epithelial repair and prevention of fibrotic remodeling.

2023-11-15 | GSE243135 | GEO

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

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

| PRJNA1399763 | ENA

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

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

| PRJNA1399762 | ENA

Expression data for 2-month-old wild type and Tfam-SCKO (MPZ-Tfam KO) sciatic nerves

Project description:Gene expression analysis of 2-month-old Ctrl and Tfam-SCKO mice. At this age mitochondrial function is disrupted in the Schwann cells of Tfam-SCKO mice ,but their nerves display only very limited pathology. Mitochondrial dysfunction is a common cause of peripheral neuropathy. Much effort has been devoted to examining the role played by neuronal/axonal mitochondria, but how mitochondrial deficits in peripheral nerve glia (Schwann cells, SCs) contribute to peripheral nerve diseases remains unclear. Here, we investigate a mouse model of peripheral neuropathy secondary to SC mitochondrial dysfunction (Tfam-SCKOs). We show that disruption of SC mitochondria activates a maladaptive integrated stress response through actions of heme-regulated inhibitor kinase (HRI), and causes a shift in lipid metabolism away from fatty acid synthesis toward oxidation. These alterations in SC lipid metabolism result in depletion of important myelin lipid components as well as in accumulation of acylcarnitines, an intermediate of fatty acid b-oxidation. Importantly, we show that acylcarnitines are released from SCs and induce axonal degeneration. A maladaptive integrated stress response as well as altered SC lipid metabolism are thus underlying pathological mechanisms in mitochondria-related peripheral neuropathies. Total RNA samples were prepared by isolating and pooling RNA from three different 2-month-old MPZ-Tfam KO and Ctrl mice. 2 replicates per genotype were used in this experiment and they were prepared entirely independently.

2013-03-13 | E-GEOD-44605 | biostudies-arrayexpress

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