Impaired Removal of the Damaged Mitochondria in the Metabolic Memory Phenomenon Associated with Continued Progression of Diabetic Retinopathy.

Abstract

Retinopathy fails to halt even after diabetic patients in poor glycemic control try to institute tight glycemic control, suggesting a "metabolic memory" phenomenon, and the experimental models have demonstrated that mitochondria continue to be damaged/dysfunctional, fueling into the vicious cycle of free radicals. Our aim was to investigate the role of removal of the damaged mitochondria in the metabolic memory. Using human retinal endothelial cells (HRECs), incubated in 20mM D-glucose for 4days, followed by 5mM D-glucose for 4 additional days, mitochondrial turnover, formation of mitophagosome, and mitophagy flux were evaluated. Mitophagy was confirmed in a rat model of metabolic memory where the rats were kept in poor glycemic control (blood glucose ~ 400mg/dl) for 3months soon after induction of streptozotocin-induced diabetes, followed by 3 additional months of good control (BG < 150mg/dl). Reversal of high glucose by normal glucose had no effect on mitochondrial turnover and mitophagosome formation, and mitophagy flux remained compromised. Similarly, 3months of good glycemic control in rats, which had followed 3months of poor glycemic control, had no effect on mitophagy flux. Thus, poor turnover/removal of the damaged mitochondria, initiated during poor glycemic control, does not benefit from the termination of hyperglycemic insult, and the damaged mitochondria continue to produce free radicals, suggesting the importance of mitophagy in the metabolic memory phenomenon associated with the continued progression of diabetic retinopathy.