FIGURE 1.

This schematic illustrates the proposed cascade of events that link the increased intraocular pressure of glaucoma to mitochondrial dysfunction and the NLRP3 inflammasome. (A) Intraocular pressure increases as a result of perturbed aqueous humor outflow in the eye. (B) Intraocular pressure increase prevents efficient blood flow to the eye, resulting in hypoxia/ischemia. During physiological conditions, hypoxia induces mitophagy to eliminate dysfunctional mitochondrial accumulation. (C) However, during glaucoma, hypoxia-induced mitophagy may be inhibited. Concomitantly, external ATP binds to and opens the cation-selective P2X7R (D). Ca²⁺ influx can stimulate mitochondrial dysfunction that will induce inflammation, activated microglia, and cytokine release. (E) Dysfunctional and fragmented mitochondria accumulate, thus promoting oxidative stress and metabolic vulnerability. Oxidative stress induces inflammasome assembly and activation as NLRP3, localized at the ER, comes into proximity to the ASC, localized at the mitochondria, on MAMs. (F) Inflammasome activation releases cytokines that establish a positive feedback loop to exacerbate further inflammatory response. (G) Aβ that has been demonstrated in mitochondria can also accumulate in axons, thereby inducing axon transport deficit that further contributes to glaucoma progression. Created with Biorender.com