PEDF improves mitochondrial function in RPE cells during oxidative stress.PURPOSE
 This study investigates the role of pigment epithelium-derived factor (PEDF) in limiting oxidative stress-induced damage to RPE cells through mitochondrial pathways.


 Three groups of early-passaged RPE cells from donors 50 to 55, 60 to 65, and 70 to 75 years old (yo) were either preconditioned with PEDF followed by exposure to sublethal doses of hydrogen peroxide (H2O2) or post-treated with PEDF after H2O2 treatment.  Effects of PEDF on mitochondrial function and cell viability were examined.


 Preconditioning or poststressed treatment with PEDF resulted in increased cell viability, inhibition of cytochrome c release and caspase 3 cleavage, and improved mitochondria function denoted by a decrease in ROS generation and increases in ATP production and ΔΨm.  Although PEDF potentiated both PI3K/Akt and MAPK signaling in the cells, stabilization of mitochondrial networks and function was dependent on its activation of PI3K/Akt.  Specificity of PEDF's activity was confirmed using the pharmacological inhibitors LY294002, SH6, and U0126.  In addition, PEDF blocked effects of oxidative stress on expression of cyclophilin D and UCP2, genes controlling mitochondrial function, and the apoptotic genes caspase 3, Bax, and Bcl2.  Control of ROS levels by PEDF was specifically linked to UCP2 regulation since PEDF-induced expression of this gene in UCP2-deficient cells was associated with a decrease in ROS production.


 We provide evidence that PEDF promotes resilience of aging RPE cells to oxidative stress by stabilizing mitochondrial networks and function and that mitochondrial dynamics in human RPE cells are controlled, in part, through the PI3K/Akt pathway.
PEDF