Chronic Hyperglycemia Compromises Mitochondrial Function in Corneal Epithelial Cells: Implications for the Diabetic Cornea.
Chronic Hyperglycemia Compromises Mitochondrial Function in Corneal Epithelial Cells: Implications for the Diabetic Cornea.
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作者：
线粒体功能障碍是导致糖尿病并发症发生的主要病理生理事件。本研究探讨了高血糖对角膜上皮细胞线粒体代谢的时间效应。为了实现这一点，将人端粒酶永生化的角膜上皮细胞培养在含有6 mM葡萄糖的限定生长培养基中。为了模拟高血糖症，在含有25 mM D-葡萄糖的培养基中培养细胞，并在甘露醇中培养对照细胞。使用代谢通量分析，24 h后线粒体呼吸出现高渗介导的增加。到第5天，在整个14天期间保持抑制的高葡萄糖细胞中的备用呼吸能力降低。虽然呼吸在第9天仍然很高，但糖酵解减少。到第14天，线粒体呼吸减少。这伴随着糖酵解恢复到正常血糖水平。这些变化包括线粒体极化减少和细胞周期停滞。总之，这些数据表明慢性而非急性高血糖应激导致线粒体功能障碍。此外，高血糖引起的备用呼吸能力的丧失降低了角膜上皮细胞对随后的应激反应的能力。线粒体功能受损代表了一种以前未探索的机制，可能导致糖尿病角膜并发症。
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.
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