ArticleScientific reports2026
ATF4 regulates mitochondrial dysfunction and mitophagy, contributing to corneal endothelial apoptosis.
Article in Scientific reports, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Article
- Gypenosides Mitigate STEC-Induced Intestinal Injury Through Modulation of Ferroptosis Involving the ATF4-CHAC1-GPX4 Axis.Antioxidants (Basel, Switzerland) · 2026Article
- Unfolded Protein Response Pathways in Cancer: Mechanisms, Tumor Biology and Therapeutic Opportunities.Molecular diagnosis & therapy · 2026Review
- Quantitative analysis of autophagic flux reveals radiation-induced activation of SQSTM1-mediated degradation of protein aggregates and ER-phagy.Journal of radiation research · 2026Article
- Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.Muscles (Basel, Switzerland) · 2026Review
- ATF4 Coordinates Transcriptomic and Structural Adaptations in Aging Muscle.bioRxiv : the preprint server for biology · 2026Article
- Role of Activating Transcription Factor 4 in Metabolic, Neurologic, and Ocular Diseases.Cells · 2026Review
- Mitochondria-Nuclear Crosstalk: Orchestrating mtDNA Maintenance.Environmental and molecular mutagenesis · 2025Review
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Abstract
Endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and mitophagy are known to contribute independently to corneal endothelial cell (CEnC) apoptosis in Fuchs’ endothelial corneal dystrophy (FECD). However, the role of a specific ER stress pathway (PERK-ATF4-CHOP) in regulating these events is unknown. This study aims to investigate the role of ATF4 in regulating mitochondrial dysfunction and mitophagy, which ultimately leads to CEnC apoptosis. Human corneal endothelial cell line (21T), Fuchs’ corneal endothelial cell line (F35T), and primary human corneal endothelial cells were treated with ER stressor tunicamycin (Tun). ATF4 siRNA was used to knock down ATF4 in 21T cell line and primary corneal endothelial cells. Mitophagy and apoptotic proteins were analyzed using Western blotting. ATF4+/− and ATF4 +/+ mice were irradiated with UVA to assess ER stress and corneal endothelial apoptosis. F35T cell line had significantly increased expression of the ER stress pathway as well as caspase-mediated apoptotic molecules compared to 21T at baseline, which further increased after Tun treatment. F35T cells exhibited significantly decreased mitochondrial ATP and MMP, and increased mitochondrial fragmentation, which was further exacerbated after Tun. F35T cells also demonstrated inhibition of mitophagy, similar to 21T, after treatment with tunicamycin, despite the upregulation of mitophagy initiators. ATF4 knockdown attenuated ER and mitochondrial stress proteins, rescued mitochondrial membrane potential (MMP) loss, downregulated mitochondrial fragmentation, activated mitophagy, and prevented CEnC death under chronic ER stress. ATF4+/− mice had increased CE numbers, with improved cellular morphology and decreased ER stress marker CHOP expression, compared to ATF4+/+ mice post-UVA. Pro-apoptotic ATF4 induction following ER stress disrupts mitochondrial function, leading to mitophagy inhibition and CEnC apoptosis. This study highlights the importance of ATF4 in ER-mitochondrial crosstalk and its contribution to CEnC apoptosis in FECD.
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