Abstract
Mitochondria are responsible for bioenergetics, metabolism and apoptosis signals in health and disease. The retina being a part of the central nervous system consumes large amounts of glucose and oxygen to generate ATP via the mitochondrial oxidative phosphorylation for its phototransduction and visual function. During ATP generation, electrons leak from the mitochondrial electron transport chain, which is captured by molecular oxygen to produce reactive oxygen species (ROS). These mtROS damage mitochondrial proteins, mtDNA, and membrane lipids and release them in the cytosol. Mitochondrial components are recognized as danger-associated molecular patterns (DAMPS) by cytosolic pattern recognition receptors such as NOD-like receptors, NLRP3 inflammasomes. They process pro-caspase-1 to active caspase-1, which cleaves pro-inflammatory IL-1β o mature IL-1β causing inflammation and cell death by pyroptosis. To counter the damaging action of mtROS and inflammasomes in fully differentiated cells in the retina, the removal of the damaged and dysfunctional mitochondria by a double-membrane autophagic process via lysosomal degradation called mitophagy is critical for mitochondrial homeostasis and cell survival. Nonetheless, under chronic diseases including diabetic retinopathy (DR), mitophagy dysregulation and NLRP3 inflammasome activation exist, which cause premature cell death and disease progression. Recently, the thioredoxin-interacting protein TXNIP, which is strongly induced by diabetes and inhibits anti-oxidant function of thioredoxin, has been implicated in mitochondrial dysfunction, mitophagic dysregulation and NLRP3 inflammasome activation in DR. Therefore, TXNIP silencing or pharmacological inhibition may normalize mitophagic flux and NLRP3 inflammasome activation, which will prevent or slow down the progression of DR.
Highlights
Diabetic retinopathy (DR) is the most common cause of blindness among the working adult population in the developed and developing countries including the US
DR is generally defined by microvascular dysfunction including endothelial dysfunction, inner blood-retinal-barrier breakdown, pericyte loss and acellular capillary formation, capillary basement membrane thickening, microaneurisms followed by formation of new fragile and leaky blood vessels, a serious form of proliferative diabetic retinopathy (PDR) and blindness [1,2]
Thioredoxin-interacting protein TXNIP has been defined as a pro-oxidative stress, proinflammatory and pro-apoptotic protein, which is strongly induced by high glucose and diabetes in most tissues examined including the pancreatic beta, renal and retinal cells [7,8,9,10]
Summary
Diabetic retinopathy (DR) is the most common cause of blindness among the working adult population in the developed and developing countries including the US. Thioredoxin-interacting protein TXNIP has been defined as a pro-oxidative stress, proinflammatory and pro-apoptotic protein, which is strongly induced by high glucose and diabetes in most tissues examined including the pancreatic beta, renal and retinal cells [7,8,9,10]. TXNIP is known to migrate to the mitochondrion and mediates mitochondrial dysfunction, membrane depolarization and release of pro-apoptotic proteins in the cytosol [12].
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