Genetic and pharmacological correction of impaired mitophagy in retinal ganglion cells rescues glaucomatous neurodegeneration

Progressive loss of retinal ganglion cells (RGCs) and degeneration of optic nerve axons are the pathological hallmarks of glaucoma. Ocular hypertension (OHT) and mitochondrial dysfunction are linked to neurodegeneration and vision loss in glaucoma. However, the exact mechanism of mitochondrial dysfunction leading to glaucomatous neurodegeneration is poorly understood. Using multiple mouse models of OHT and human eyes from normal and glaucoma donors, we show that OHT induces impaired mitophagy in RGCs, resulting in the accumulation of dysfunctional mitochondria and contributing to glaucomatous neurodegeneration. Using mitophagy reporter mice, we show that impaired mitophagy precedes glaucomatous neurodegeneration. Notably, the pharmacological rescue of impaired mitophagy via Torin-2 or genetic upregulation of RGC-specific Parkin expression restores the structural and functional integrity of RGCs and their axons in mouse models of glaucoma and ex-vivo human retinal-explant cultures. Our study indicates that impaired mitophagy contributes to mitochondrial dysfunction and oxidative stress, leading to glaucomatous neurodegeneration. Enhancing mitophagy in RGCs represents a promising therapeutic strategy to prevent glaucomatous neurodegeneration. Graphical Abstract