IGF-1 Signaling Modulates Oxidative Metabolism and Stress Resistance in ARPE-19 Cells Through PKM2 Function

Abstract

The retinal pigment epithelium (RPE) contributes to retinal homeostasis, and its metabolic dysfunction is implied in the development of retinal degenerative disease. The isoform M2 of pyruvate kinase (PKM2) is a key factor in cell metabolism, and its function may be affected by insulin-like growth factor 1 (IGF-1). This study aims to investigate the effect of IGF-1 on PKM2 modulation of RPE cells and whether co-treatment with klotho may preserve it. ARPE-19 cells, an ex vivo model of human pigmented epithelium, were exposed to IGF-1. Then, we evaluated PKM2 expression, dimerization and subcellular localization, energy metabolism, and redox balance, and whether pre-treatment with Klotho may antagonize the effects of IGF-1. The results show that IGF-1 favors PKM2 dimerization, thus reducing the activity of PKM2 and leading to an altered cellular energy status coupled with reduced oxidative stress. In conclusion, PKM2 plays a pivotal role in the modulation of RPE metabolism and redox balance and could explain the mechanisms through which IGF-1 participates in the pathogenesis of some retinal diseases. Klotho may exert protective effects by mitigating the IGF-1 signal and its effect on mitochondrial function.