Hyperglycemia Promotes Mitophagy and Thereby Mitigates Hyperglycemia-Induced Damage

Diabetic retinopathy (DR) is one of the microvascular complications of diabetes mellitus (DM). The majority of patients with DM eventually develop some degree of DR. The observation that DR typically takes decades to develop suggests the existence of an endogenous system that protects from diabetes-induced damage. We posit that failure of this system is a prerequisite for DR, and its persistence underlies the extended delay (>50 years) of DR in medalists, which is unrelated to glycemic control. To investigate if such a system exists in primary human retinal endothelial cells (HRECs), we cultured them in either normal (5 mM, NG), or high (30 mM, HG) glucose. We observed that prolonged exposure to HG was beneficial instead of detrimental. While TNFα -induced expression of VCAM1 and ICAM1 was unaffected after 1 day of HG, it waned as the exposure to HG was extended. Similarly, oxidative stress-induced death decreased as exposure to HG was prolonged. Furthermore, mitochondrial functionality, which was compromised by 1 day of HG, was improved by 10 days of HG, and this change required increased clearance of damaged mitochondria (mitophagy). Finally, antagonizing mitochondrial dynamics compromised the cells’ ability to endure HG: susceptibility to cell death increased, basal barrier function and responsiveness to VEGF deteriorated. These observations indicate the existence of an endogenous system that protects HRECs from the deleterious effects of HG. Hyperglycemia-induced mitochondrial adaptation (HIMA) is a plausible contributor to the mechanism responsible for the delayed onset of DR; loss of HIMA may set the stage for the development of DR. Recent studies with Medalists, patients with DM who are resistant to complications for 50 years or more, investigated endogenous protective systems. Resistance to diabetic nephropathy (DN) in these patients was associated with increased glycolysis. Like the retina, the functionality of the kidney is jeopardized by the development of diabetes, and DN develops only after many years of diabetes. We found that a metabolic switch was associated with the acquisition of HIMA. HG elevated glycolysis, and metabolite analysis revealed elevated amounts of PPP metabolites - G6P/F6P/G1P and D-ribose-1/5-phosphate/D-ribulose 5-phosphate. Reducing both glycolysis and pentose phosphate pathway (PPP) in HG cells (to the NG level) with 2-DG initially eliminated a key feature of HIMA - enhanced mitochondrial redox capacity. Further treatment resulted in increased mitochondrial oxidative stress and basal cell death in response to HG. However, the effect of 2-DG on mitophagy was inconclusive. These observations indicate that elevated glycolysis and PPP are partially required for HIMA and, therefore, potentially protect the retinal vasculature from the development of DR.