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

Diabetes can result in impaired corneal wound healing. Mitochondrial dysfunction plays an important role in diabetic complications. However, the regulation of mito-chondria function in the diabetic cornea and its impacts on wound healing remain elusive. The present study aimed to explore the molecular basis for the disturbed mitochondrial metabolism and subsequent wound healing impairment in the diabetic cornea. Seahorse analysis showed that mitochondrial oxidative phosphorylation is a major source of ATP production in human corneal epithelial cells. Live corneal biopsy punches from type 1 and type 2 diabetic mouse models showed impaired mitochondrial functions, correlating with impaired corneal wound healing, compared to nondiabetic controls. To approach the molecular basis for the impaired mitochon-drial function, we found that Peroxisome Proliferator-Activated Receptor-& alpha; (PPAR & alpha;) expression was downregulated in diabetic human corneas. Even without diabetes, global PPAR & alpha; knockout mice and corneal epithelium-specific PPAR & alpha; conditional knockout mice showed disturbed mitochondrial function and delayed wound healing in the cornea, similar to that in diabetic corneas. In contrast, fenofibrate, a PPAR & alpha; agonist, ameliorated mitochondrial dysfunction and enhanced wound healing in the corneas of diabetic mice. Similarly, corneal epithelium-specific PPAR & alpha; transgenic overexpression improved mitochondrial function and enhanced wound healing in the cornea. Furthermore, PPAR & alpha; agonist ameliorated the mitochondrial dysfunction in primary human corneal epithelial cells exposed to diabetic stressors, which was impeded by siRNA knockdown of PPAR & alpha;, suggesting a PPAR & alpha;-dependent mech-anism. These findings suggest that downregulation of PPAR & alpha; plays an important role in the impaired mitochondrial function in the corneal epithelium and delayed corneal wound healing in diabetes.