Biology subjects

Kliment, C. R.

Publications and source records attributed to Kliment, C. R..

2 recordsLinked to original sources

bioRxiv2026

Adenine nucleotide translocase 2 (ANT2) deficiency reprograms ferroptosis in alveolar progenitor cells to promote emphysema

Stem cell dysfunction and loss of renewal capacity are primary characteristics of tissue aging and decremental regeneration in response to injury. Alveolar type 2 cells (AT2) are key progenitor cells responsible for lung repair and are thought to be dysfunctional in diseases such as chronic obstructive pulmonary disease (COPD). AT2 cells are highly metabolic and rely on mitochondria, but how mitochondrial mechanisms influence their maintenance and cell fate is unclear. This gap is critical as no current therapies target lung repair or mitochondrial function in COPD. Here, we report that adenine nucleotide translocase 2 (ANT2), a key ATP/ADP transporter, is reduced in AT2 cells from COPD lungs, and that ANT2 loss impairs bioenergetics (ATP). We also identify, for the first time, ferroptotic susceptibility as a consequence of ANT2 loss in AT2 cells, leading to impaired self-renewal and progenitor capacity in alveolar organoids. Together, loss of ANT2 and the associated cellular dysfunction resulted in worsened lung damage or emphysema due to cigarette smoke in mice. Therapeutic restoration of ANT2 expression resulted in renewed AT2 stem cell function and prevention of emphysema by reducing oxidative stress and ferroptosis. These findings highlight the importance of ANT2 in metabolic regulation, plasticity, and cell resiliency of AT2 cells in the lung and that ANT2 is a potential target for lung repair. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/737954v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@7193bborg.highwire.dtl.DTLVardef@9a0446org.highwire.dtl.DTLVardef@18e9f5corg.highwire.dtl.DTLVardef@805a05_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2026

Alveolar Epithelial Cell Loss of the Mitochondrial Regulator TFAM Drives Progressive Lung Fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterized by failed alveolar epithelial repair and progressive fibrotic remodeling. Although aberrant reprogramming of alveolar type 2 (AT2) cells and accumulation of transitional AT2 states are increasing recognized as central features of IPF, the epithelial-intrinsic mechanisms that initiate these pathogenic states remain incompletely understood. Here, we identify mitochondrial transcription factor A (TFAM), a regulator of mitochondrial DNA maintenance, as a critical regulator of AT2 cell homeostasis. TFAM expression was reduced in AT2 cells from human IPF lungs. Inducible AT2 cell-specific Tfam deletion in mice caused spontaneous fibrotic remodeling and increased susceptibility to bleomycin-induced lung injury. TFAM-deficient AT2 cells acquired KRT8+ transitional and p21+ senescence-associated features before the onset of fibrotic transformation, accompanied by impaired oxidative phosphorylation, redox imbalance, mitochondrial superoxide accumulation, repression of mtDNA-encoded respiratory genes, and disrupted mitochondrial ultrastructure. TFAM-deficient AT2 cells developed a profibrotic secretory program that promoted extracellular matrix deposition and fibroblast activation. We further identified insulin-like growth factor-binding protein 2 (IGFBP2) as a secreted mediator induced in TFAM-deficient AT2 cells. IGFBP2 was elevated in AT2 cells in human IPF lung tissue and bronchoalveolar lavage fluid (BALF) from patients with IPF. IGFBP2 was detected in supernatants from fibrotic human precision-cut lung slices (hPCLS). IGFBP2 neutralization attenuated profibrotic remodeling in fibrotic hPCLS. Collectively, our findings identify TFAM-dependent mitochondrial homeostasis as an epithelial checkpoint linking AT2 cell-state stability to impaired epithelial-mesenchymal crosstalk driving pulmonary fibrosis.

pathology↗