Authors : Inass Bargaa
DOI : 10.25258/ijddt.16.65s.112
Volume : 16
Issue : 65
Year : 2026
Page No : 13
Axonal degeneration, mitochondrial malfunction, and a gradual loss of retinal ganglion cells are the hallmarks of glaucoma, a major cause of irreversible blindness. While Nrf2 signaling is known to shield cells from oxidative stress, little is known about how it affects the metabolic relationship between Müller glia and retinal ganglion cells. Prior research has mostly concentrated on static measurements of mitochondrial health without capturing dynamic glial-neuronal metabolic exchange. To address this, we created a quantitative framework that uses Müller cell-specific Nrf2 activation, stable isotope tracing, fluorescence-activated nuclear sorting, real-time mitochondrial imaging, spatial transcriptomics, and computational modelling to assess how glial metabolic changes affect neuronal mitochondrial function. Metabolic fluxes (lactate, glutamine, and α-Ketoglutarate (αKG)) were monitored, and retinal ganglion cell mitochondrial health was evaluated by ATP/ADP FRET biosensors, mito-Dendra2 imaging of fusion/fission dynamics, and mitophagy evaluation. Activating Nrf2 in Müller cells led to increased glutamine and αKG transfer to neurons, decreased reliance on lactate- derived substrates, improved mitochondrial function, increased ATP/ADP ratios, promoted mitochondrial network connectivity, decreased mitophagic activity, and preserved axonal structure. Computational modelling revealed a quantitative relationship between glial metabolic output and neuronal mitochondrial health, predicting retinal nerve fiber layer degeneration using mitochondrial characteristics. These results highlight Nrf2-driven Müller cell metabolic reprogramming as a promising target for neuroprotective therapies in glaucoma and lay the groundwork for investigating metabolic interventions in other retinal and neurodegenerative diseases characterized by mitochondrial dysfunction. They also show that the survival of retinal ganglion cells depends on both intrinsic neuronal mechanisms and the quality of glial metabolic support.