Chronic Hyperglycemia Compromises Mitochondrial Function in Corneal Epithelial Cells: Implications for the Diabetic Cornea

Abstract

Mitochondrial dysfunction is a major pathophysiological event leading to the onset of diabetic complications. This study investigated the temporal effects of hyperglycemia on mitochondrial metabolism in corneal epithelial cells. To accomplish this, human telomerase-immortalized corneal epithelial cells were cultured in a defined growth medium containing 6 mM glucose. To simulate hyperglycemia, cells were cultured in a medium containing 25 mM D-glucose, and control cells were cultured in mannitol. Using metabolic flux analysis, there was a hyperosmolar-mediated increase in mitochondrial respiration after 24 h. By day 5, there was a decrease in spare respiratory capacity in cells subject to high glucose that remained suppressed throughout the 14-day period. Although respiration remained high through day 9, glycolysis was decreased. Mitochondrial respiration was decreased by day 14. This was accompanied by the restoration of glycolysis to normoglycemic levels. These changes paralleled a decrease in mitochondrial polarization and cell cycle arrest. Together, these data show that chronic but not acute hyperglycemic stress leads to mitochondrial dysfunction. Moreover, the hyperglycemia-induced loss of spare respiratory capacity reduces the ability of corneal epithelial cells to respond to subsequent stress. Compromised mitochondrial function represents a previously unexplored mechanism that likely contributes to corneal complications in diabetes.

Mitochondria Transplantation Promotes Corneal Epithelial Wound Healing

“…Mitochondria serve as the main source of cellular energy in the cornea and play a critical role in corneal wound healing. 4 – 6 , 8 , 9 Moreover, common causes of corneal insults, such as UV light exposure, oxidative stress, chemical injury, and epithelial debridement, compromise mitochondrial integrity, dynamics, and function. 4 , 6 , 37 , 38 Interestingly, restoration of corneal mitochondrial respiration has been linked to corneal wound healing.…”

“… 8 Furthermore, in diabetic corneas, high glucose-induced hyperosmolarity was found to reduce mitochondrial respiration in corneal epithelial cells and negatively impact migration. 9 …”

Peroxisome proliferator-activated receptor-α (PPARα) regulates wound healing and mitochondrial metabolism in the cornea

“…Mussi et al. showed high-glucose culture compromises mitochondrial function in human telomerase-immortalized corneal epithelial cells ( 35 ). Aldrich et al.…”

Irisin Ameliorates Renal Tubulointerstitial Fibrosis by Regulating the Smad4/β-Catenin Pathway in Diabetic Mice

“…The pathophysiology of diabetic complications, including DKD, is greatly influenced by mitochondrial dysfunction. 34 Altered mitochondrial function in major dysfunctional organs is known to cause obesity and diabetic manifestations in animals and humans. 35 For instance, HG or UCP2 overexpression plasmid resulted to mitochondrial fragmentation, indicating enhanced mitochondrial fission and dysfunction, as demonstrated by our prior studies.…”