The retina being a part of the central nervous system consumes large amounts of glucose and oxygen to generate ATP for its visual function. During ATP generation in the mitochondrial electron transport chain, mitochondrial Reactive Oxygen Species (mtROS) is generated as a byproduct. Although anti-oxidants are present in the mitochondrion to counter free radicals, excess mtROS causes damage to mitochondrial proteins, mtDNA, and membrane lipids. Furthermore, damaged mitochondria are inefficient in ATP production but continue to release ROS. Mitochondrial components, when released into the cytosol, are recognized as Danger-Associated Molecular Patterns (DAMPS) by pattern recognition NOD-like receptors including the NLRP3 inflammasome. NLRP3 inflammasomes process inactive pro-caspase-1 to an active caspase-1, which cleaves pro-inflammatory IL-1β to mature IL-1β causing inflammation and premature cell death. To counter the damaging action of mtROS and inflammasomes in fully differentiated retinal cells, the removal of dysfunctional mitochondria is needed by mitophagy, a specific form of lysosomal degradation via autophagy. Nonetheless, mitophagy deregulation, lysosome destabilization and NLRP3 inflammasome activations occur in Diabetic Retinopathy (DR) causing chronic inflammation and disease progression. Recently, the Thioredoxin-interacting protein, TXNIP, has been shown to be induced strongly by high glucose and diabetes inhibiting the anti-oxidant function of Thioredoxin. Subsequently, TXNIP causes mitochondrial dysfunction, oxidative stress, mitophagy deregulation, lysosome destabilization and inflammation in DR. Therefore, gene therapies targeting TXNIP, NLRP3 and/or the redox system have potentials to prevent/slow down retinal damages in DR.
Keywords: Diabetic Retinopathy; Gene Therapy; Lysosomal Destabilization; Mitophagic Flux; NLRP3 Inflammasome; TXNIP.