Figure 6: TXNIP overexpression and potential mechanisms for the pathogenesis of diabetic retinopathy. (i) Diabetes and hyperglycemiainduced TXNIP expression may initially be a stress response and protective event, which involves generation of a mild oxidative/nitrosative stress by trapping Trx. This process may induce anti-oxidant gene expression and reprogramming of glucose utilization by glycolysis and mitochondrial oxidative phosphorylation, which enhance the pentose phosphate pathway (PPP) and NADPH synthesis. Simultaneously, a mild ER-stress may be induced to activate er-UPR and anti-oxidant and chaperone synthesis. (ii) As hyperglycemia persists, TXNIP up-regulation sustains leading to ROS/RNS and er-stress. Stressed ER releases stored calcium, which is taken up by mitochondria, leading to mitochondrial dysfunction. Damaged mitochondria release ROS from its electron transfer in ETC and they are inefficient in ATP production. Mitophagy is thus activated to remove damaged mitochondria and maintain MT homeostasis as a survival mechanism. (iii) In addition, damaged mitochondria release cytochrome c and activate pro-apoptotic caspase-3. (iv) Nonetheless, apoptosis is an energy consuming process and requires MT ATP synthesis for packaging cytosolic and nuclear components by membrane vesicles. As the MT bioenergetics collapse and ATP is depleted, apoptosis gives way to necroptosis or pyroptosis. These latter cell death mechanisms involve plasma membrane leakage and release of cellular contents as DAMPs (damage associated molecular patterns). DAMPs are recognized by cytosolic and membrane bound pattern recognition receptors (PRRs) in innate immune cells (such as microglia, Muller glia, as well as by epithelial cells) as danger signals or alarmins, which evoke innate immune responses and inflammation. (v) As diabetes progresses and ROS/RNS stress prevails, the initial cellular anti-oxidant and chaperone capacity weaken and cell defensive mechanisms fail, a process known as hormesis - beneficial at low level and harmful at prolonged and higher level [162] - leading to disease progression of diabetic retinopathy. Therefore, TXNIP overexpression may play a critical role in cellular oxidative/nitrosative stress, inflammation, pre-mature cell death and progression of microvascular complications of diabetes including diabetic retinopathy. Thus, TXNIP represents a novel target for gene and drug therapies to prevent or slow down the progression of diabetic retinopathy.