AMP-activated-protein kinase (AMPK) is an essential sensor and metabolic regulator of retinal neurons and their integrated metabolism with RPE

Abstract

15The retina has one of the highest energy demands in the human body, and proper 16 regulation of metabolism among the cell types of the retina is required for functional vision. 17Recent studies have reported that retinal metabolism is disrupted during retinal degeneration 18 and aging, while therapies designed to enhance metabolism can slow or prevent degeneration. 19Here, we show that multiple metabolic pathways, including those regulated by a key ATP sensor 20 and regulator of metabolism, AMP-activated-kinase (AMPK), were dysregulated in a model of 21 inherited retinal degeneration. In order to assess the direct role of AMPK in regulating retinal 22 metabolism, we used mice with retina-specific knockout of AMPK activity. Conditional loss of 23 AMPK resulted in impaired visual function at an early age, with slow photoreceptor loss 24 observed in older mice. Moreover, we found that loss of AMPK resulted in decreased metabolic 25 flux from glucose, decreased mitochondrial DNA copy number, decreased mitochondrial-related 26 gene expression, and alterations in mitochondrial morphology in the photoreceptors, all of which 27 preceded degeneration. Surprisingly, metabolic changes from the loss of AMPK in retinal 28 neurons also resulted in secondary degeneration of retinal pigment epithelial (RPE) cells. 29Together, these data show that AMPK signaling is important for maintaining metabolic 30 homeostasis of the retina and support the hypothesis that photoreceptors and RPE have a 31 shared metabolic ecosystem that is controlled, in part, by AMPK. 32 33 Main 34 The central nervous system, including the retina, is often cited as having one of the 35 highest energy demands in the body, with pathways that require utilization of ATP, glucose, 36 lactate, fatty acids, glutathione (GSH), and NADPH for proper neuronal function and protection 37 against retinal degeneration 1-4 . As much as half of the metabolites and metabolic activity in the 38 retina are located in the light-sensitive photoreceptors 5,6 . ATP is heavily consumed by NaK-39 ATPases in photoreceptors to maintain the ion gradient within the cells, and a considerable 40 amount of energy is dedicated to supporting phototransduction in response to light 1,2 . While 41 disruption of metabolism has been associated with retinal degeneration, manipulations that 42 restore energy homeostasis by enhancing glycolysis or mitochondrial activity can preserve 43 retinal function and promote photoreceptor survival 7-12 . 44 However, little is known about how metabolic activity is regulated in the retina. The 5' 45 adenosine monophosphate-activated protein kinase (AMPK) pathway is a logical control 46 mechanism for high metabolic activity in cells. AMPK is an evolutionarily conserved 47 EY016459, the Foundation Fighting Blindness, and an unrestricted grant from Research to 388 Prevent Blindness. The authors wish to acknowledge the contributions of Lena Phu for her 389 assistance in genotyping, qRT-PCR, and measuring ONL thicknesses. The authors also wish to 390 acknowledge the...