Modulation of Iron-Induced Glucose Metabolic Reprogramming Alleviates Retinal Pigment Epithelial Cell Senescence

Area of Science:

• Ophthalmology
• Cell Biology
• Metabolic Research

Background:

• Iron overload is implicated in various pathologies.
• Retinal pigment epithelial (RPE) cells are crucial for retinal health.
• Cellular senescence contributes to age-related diseases.

Purpose of the Study:

• To investigate if iron overload induces RPE cell senescence via glucose metabolic reprogramming.
• To explore therapeutic strategies targeting this metabolic pathway.

Main Methods:

• Utilized human iPSC-derived RPE cells and mouse models.
• Assessed mitochondrial function, ROS, and senescence markers using various assays.
• Modulated glucose metabolism with inhibitors (2-DG, PKM2-IN-1) and enhancers (SO).

Main Results:

• Iron overload induced a metabolic shift in RPE cells, increasing glucose flux and ROS production, leading to senescence.
• Inhibiting the metabolic surge with 2-DG or PKM2-IN-1 attenuated senescence and preserved mitochondrial function.
• Enhancing pyruvate flux exacerbated senescence, while 2-DG protected RPE cells in vivo, preserving visual function.

Conclusions:

• Glucose metabolic reprogramming drives iron-induced RPE senescence through ROS-mediated mitochondrial damage.
• Targeting glucose metabolism offers a potential therapeutic approach for RPE degeneration in conditions like age-related macular degeneration.