Glial metabolic alterations during glaucoma pathogenesis

Glaucoma is the leading cause of irreversible blindness. Current treatment options are limited and often only slow disease progression. Metabolic dysfunction has recently been recognized as a key early and persistent mechanism in glaucoma pathophysiology. Several intrinsic metabolic dysfunctions have been identified and treated in retinal ganglion cells to provide neuroprotection. Growing pre-clinical and clinical evidence has confirmed that metabolic alterations in glaucoma are widespread, occurring across visual system tissues, in ocular fluids, in blood/serum, and at the level of genomic and mitochondrial DNA. This suggests that metabolic dysfunction is not constrained to retinal ganglion cells and that metabolic alterations extrinsic to retinal ganglion cells may contribute to their metabolic compromise. Retinal ganglion cells are reliant on glial metabolic support under normal physiological conditions, but the implications of metabolic dysfunction in glia are underexplored. We highlight emerging evidence that has demonstrated metabolic alterations occurring within glia in glaucoma, and how this may affect neuro-glial metabolic coupling and the metabolic vulnerability of retinal ganglion cells. In other neurodegenerative diseases which share features with glaucoma, several other glial metabolic alterations have been identified, suggesting that similar mechanisms and therapeutic targets may exist in glaucoma.