bims-mideyd 2025-07-27 papers

Curr Issues Mol Biol. 2025 Mar 26. pii: 224. [Epub ahead of print]47(4):

Tauroursodeoxycholic Acid Confers Protection Against Oxidative Stress via Autophagy Induction in Retinal Pigment Epithelial Cells.

Daniella Zubieta, Cassandra Warden, Sujoy Bhattacharya, Milam A Brantley.

Tauroursodeoxycholic acid (TUDCA) has been shown to protect against oxidative damage in retinal pigment epithelial (RPE) cells. However, the mechanisms by which it mediates these protective effects have not been thoroughly investigated in the context of age-related macular degeneration (AMD) disease onset and progression. We measured LC3-II and p62 expression via Western blot and immunohistochemistry in RPE cells treated with H2O2, TUDCA, or a combination of both to measure autophagy induction. To determine autophagy flux, we measured the expression of LC3-II/LC3-I in RPE cells in the presence of bafilomycin via Western blot. To determine the mechanistic pathways of TUDCA-induced autophagy, we measured the protein expression of autophagy regulators (Atg5, Beclin-1, S6, AMPK, and Akt) via Western blot. We show that TUDCA-mediated autophagy induction confers protection of RPE cells against oxidative damage via mTORC1/mTORC2 independent pathways but depends on Atg5. Our work adds to the overall understanding of RPE cell homeostasis and highlights the role of TUDCA in maintaining RPE health.

Keywords: age-related macular degeneration; autophagy; oxidative stress; retinal pigment epithelial cells; tauroursodeoxycholic acid

DOI: https://doi.org/10.3390/cimb47040224

Free Radic Biol Med. 2025 Jul 16. pii: S0891-5849(25)00840-8. [Epub ahead of print]239 27-42

MITF promotes MFN2-dependent mitochondrial fusion to protect retinal pigment epithelial cells from mitochondrial damage.

Ying-Ao Chen, Wan-Ni Lu, Pingping Li, Tianyin Nie, Yan Li, Rui Zeng, Sen Lin, Meiling Gao, J Fielding Hejtmancik, Ling Hou, Xiaoyin Ma.

There is growing indication that protecting the retinal pigment epithelium (RPE) against mitochondrial damage is crucial for preventing RPE cell dysfunction and retinal degeneration. However, the molecular mechanisms remain largely unknown. Here, we show that microphthalmia-associated transcription factor (MITF), a potent antioxidant inducer in RPE, promotes mitochondrial fusion in RPE cells and protects them from mitochondrial uncoupler carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-induced mitochondrial damage in ARPE-19 or mouse primary RPE cells ex vivo and Mitf heterozygous mice (Mitf-/+), Mitf-overexpressing transgenic mice (Dct-Mitf) or AAV mediated MITF overexpression mice in vivo. Mechanistically, MITF directly binds to the promoter of Mitofusin 2 (MFN2), a mitochondrial membrane protein that participates in mitochondrial fusion, and activates its transcription. Conversely, the knockdown of MFN2 neutralized the effects of MITF on mitochondrial fusion and mitochondrial damage protection. Intravitreal injection of mitochondria-targeted SkQ-1 nanoparticles effectively protects RPE cells from CCCP-induced damage in the Mitf-/+ mice in vivo. These findings suggest that MITF has an important role in regulating mitochondrial fusion in RPE cells and provides new insights into understanding the mechanisms of MITF deficiency induced RPE abnormalities and retinal degeneration.

Keywords: MITF; Mitochondria; Mitochondrial fusion; RPE; Retinal degeneration

DOI: https://doi.org/10.1016/j.freeradbiomed.2025.07.025

J Cell Mol Med. 2025 Jul;29(14): e70693

A PEDF-Derived Short Peptide Prevents Sodium Iodate-Induced Retinal Degeneration in Rats by Activating the SLC7A11/GSH/GPX4 Pathway in the RPE Cells.

Tsung-Chuan Ho, Shawn-H Tsai, Shu-I Yeh, Ming-Hui Sun, Yeou-Ping Tsao.

Retinal pigment epithelial (RPE) cell damage caused by oxidative stress is a key factor in the pathogenesis of dry age-related macular degeneration (AMD). 6dS peptide is derived from the neuroprotective motif of pigment epithelium-derived factor (PEDF) and has antioxidant effects. This study used the sodium iodate (SI, a chemical oxidant)-induced animal dry AMD model to investigate the 6dS-mediated antioxidant mechanism. 6dS reduced SI-induced cytotoxicity, including ferrous iron accumulation, lipid peroxidation, glutathione (GSH) depletion, and ferroptosis in ARPE-19 cells. SI injection in rats induced cell death and lipid peroxidation in the RPE layer, along with retinal atrophy and electrophysiological dysfunction, recapitulating features of dry AMD that were counteracted by 6dS eye drop treatment. Mechanistically, 6dS induced the expression of SLC7A11 (solute carrier family seven member 11) and glutathione peroxidase 4 (GPX4) to alleviate SI-induced GSH depletion and lipid peroxidation. Inhibitors targeting the PEDF receptor, SLC7A11, and GPX4 abolished the 6dS effect. Our study proposes an antioxidant mechanism through which PEDF receptor signalling links to the SLC7A11/GSH/GPX4 axis to alleviate intracellular redox imbalance. These findings suggest that 6dS eye drops may be a promising treatment for dry AMD.

Keywords: AMD; PEDF; RPE; ferroptosis; peptide drug; sodium iodate

DOI: https://doi.org/10.1111/jcmm.70693

Acta Ophthalmol. 2025 Jul 19.

Secretory autophagy and epithelial-to-mesenchymal transition in cadaveric AMD samples: Novel pathways in disease progression.

Iswariyaraja Sridevi Gurubaran, Ali Koskela, Hanna Heloterä, Kai Kaarniranta.

PURPOSE: To examine the presence of secretory autophagy and epithelial-mesenchymal transition (EMT) in the macular retinal pigment epithelium (RPE) of human cadaver eyes with different forms of age-related macular degeneration (AMD).
METHODS: Human cadaver macula samples representing dry and wet AMD, as well as age-matched controls, were analyzed using immunohistochemistry. Markers of secretory autophagy, EMT, and inflammation were evaluated in RPE cells.
RESULTS: Increased expression of proteins associated with secretory autophagy and EMT was detected in the RPE of AMD samples compared to controls. These changes were observed in both dry and wet AMD forms.
CONCLUSION: Secretory autophagy and EMT are elevated in the macular RPE of AMD-affected eyes. These observations offer novel insight into AMD progression and potential therapeutic approaches.

Keywords: aging; drusen; epithelial degeneration; epithelial‐mesenchymal transition; macula; secretory autophagy

DOI: https://doi.org/10.1111/aos.17558