Glaucoma is a condition of progressive blindness driven by the death of retinal cells and degeneration of the optic nerve. It is driven by increased pressure in the aqueous humor, which fills a fluid compartment behind the cornea and also flows into the rest of the interior of the eye. Aqueous humor is produced at some pace in the ciliary processes of the interior of the eye, and drains at some pace through structures known as the trabecular meshwork at the front of the eye. Creation and drainage must be balanced to maintain pressure, but with age, drainage can become significantly impaired because of structural changes in the trabecular meshwork, causing pressure in the eye to increase. That increased pressure places stress on the structures of the back of the eye, ultimately leading to retinal cell death and blindness.
In today's open access paper, researchers investigate how exactly retinal cells die in the environment of excessive intraocular pressure. They provide evidence for high pressure to be disruptive to mitochondrial function in retinal cells, an effect that appears to arise because high pressure sabotages the processes of autophagy that help to maintain mitochondrial function by selectively destroying worn and malfunctioning mitochondria. When this mitochondrial quality control is significantly impaired, cells become overtaken by poorly functioning mitochondria and eventually die. The researchers show that pharmacological restoration of autophagy to more helpful levels via a small molecule mTOR inhibitor reduces the harm done to retinal cells by excess intraocular pressure, preserving mitochondrial function and cell function in the retina.
Progressive loss of retinal ganglion cells (RGCs) and degeneration of optic nerve (ON) axons are the key pathological hallmarks of glaucoma, the leading cause of irreversible blindness. Elevated intraocular pressure (IOP), primarily due to dysfunction of the trabecular meshwork ™, remains the most significant and only known modifiable risk factor. However, vision loss persists in some patients despite effective IOP control, highlighting the critical need to elucidate the mechanisms driving glaucomatous neurodegeneration. Emerging evidence links mitochondrial dysfunction to glaucomatous neurodegeneration, yet the precise mechanisms remain poorly defined. Here, we investigate whether defective autophagy/mitophagy, which removes damaged mitochondria, contributes to mitochondrial accumulation, oxidative stress, and neurodegeneration in glaucoma.
Glucocorticoid (GC)-induced and myocilin (MYOC)-associated glaucoma mouse models were used to assess the expression of mitochondrial markers in retinal tissues. Transmission electron microscopy (TEM) was employed to analyze mitochondrial accumulation. Chronic IOP elevation led to increased mitochondrial accumulation, oxidative DNA damage, and impaired mitophagy/autophagy in glaucomatous retina. TEM analysis further confirmed the accumulation of structurally abnormal mitochondria in glaucomatous ON. In mice, chronic IOP elevation significantly reduced mitophagy flux prior to RGC loss, indicating that mitophagy impairment precedes neurodegeneration.
Interestingly, enhancing autophagy using the pharmacological mTOR inhibitor Torin 2 restored mitochondrial health and prevented glaucomatous neurodegeneration in both mouse model of glaucoma and ex vivo cultured human retinal explants. Our results demonstrate that impaired autophagy and mitochondrial turnover drive glaucomatous neurodegeneration, while enhancing autophagy restores mitochondrial function and promotes neuroprotection.
View the full article at FightAging
