Mercy Pawar

Photoreceptor metabolic reprogramming provides survival advantage in acute stress while causing chronic degeneration

Photoreceptor death is the root cause of vision loss in many retinal disorders, and there is an unmet need for neuroprotective modalities to improve photoreceptor survival. The biosynthetic requirement of photoreceptors is among the highest in the body, and to meet this demand, photoreceptors maintain their ability to perform aerobic glycolysis. This highly regulated form of glycolysis allows cells to efficiently budget their metabolic needs and may be a critical link between photoreceptor function and survival. Pyruvate kinase muscle isozyme 2 (PKM2) is a key regulator of aerobic glycolysis. In the present study, we characterized the effect of PKM2 deletion on baseline functioning and survival of photoreceptors over time by utilizing a photoreceptor-specific, PKM2 knockout mouse model. We found that upon PKM2 deletion, PKM1 is upregulated in the outer retina and there is increased expression of genes involved in glucose metabolism, which led to chronic degenerative changes in the outer retina of these mice. We also discovered that this metabolic reprogramming provided a survival advantage to photoreceptors in an experimental model of retinal detachment. This study strongly supports the hypothesis that reprogramming metabolism may be a novel therapeutic strategy for photoreceptor neuroprotection during acute stress.

FAS apoptotic inhibitory molecule 2 is a stress-induced intrinsic neuroprotective factor in the retina

We report the neuroprotective role of FAS apoptotic inhibitory molecule 2 (FAIM2), an inhibitor of the FAS signaling pathway, during stress-induced photoreceptor apoptosis. Retinal detachment resulted in increased FAIM2 levels in photoreceptors with higher amounts detected at the tips of outer segments. Activation of FAS death receptor via FAS-ligand led to JNK-mediated FAIM2 phosphorylation, decreased proteasome-mediated degradation and increased association with the FAS receptor. Photoreceptor apoptosis was accelerated in Faim2 knockout mice following experimental retinal detachment. We show that FAIM2 is primarily involved in reducing stress-induced photoreceptor cell death but this effect was transient. FAIM2 was found to interact with both p53 and HSP90 following the activation of the FAS death pathway and FAIM2/HSP90 interaction was dependent on the phosphorylation of FAIM2. Lack of FAIM2 led to increased expression of proadeath genes Fas and Ripk1 in the retina under physiologic conditions. These results demonstrate that FAIM2 is an intrinsic neuroprotective factor activated by stress in photoreceptors and delays FAS-mediated photoreceptor apoptosis. Modulation of this pathway to increase FAIM2 expression may be a potential therapeutic option to prevent photoreceptor death.