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

Abstract

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.The retina has two circulations-retinal, for the inner retinal neurons, and choroidal, which through the retinal pigment epithelium (RPE), feeds the outer retina. Inner retinal neurons are exquisitely sensitive to ischemia, and irreversible inner retinal injury occurs after 2-4 hours of central retinal artery occlusion 1 . On the other hand, the choroidal circulation supplies the outer retina where the photoreceptors are located. Photoreceptors are therefore deprived of oxygen and glucose when they separate from the underlying retinal pigment epithelium, which occurs in retinal detachment. Unlike inner retinal neurons, photoreceptors are able to withstand prolonged periods of oxygen and nutrient deprivation, as demonstrated by numerous clinical studies that show visual gain when the retina is re-apposed to RPE surgically within days to weeks after initial retinal detachment symptoms 2-4 . It is hypothesized that this survival may be largely secondary to the specific metabolic demands and metabolic machinery present in the photoreceptors.Warburg and colleagues first demonstrated that neoplastic cells convert glucose to lactate despite the presence of oxygen, which is known as aerobic glycolysis or the Warburg effect 5 . In these cells, aerobic glycolysis functions to meet the high demand for metabolic energy and biosynthetic intermediates. Interestingly, Warburg noted that the retina was the only non-proliferative tissue that was capable of aerobic glycolysis and further studies showed that this effect is limited to the photoreceptors [5][6][7][8] . It has been hypothesized that the constant turnover of photoreceptor outer segments, with its extremely high metabolic requirements, drives aerobic glycoly...

Symmetric arrangement of mitochondria:plasma membrane contacts between adjacent photoreceptor cells regulated by Opa1

“…Photoreceptors are highly sensitive to hypoxia and nutrient deprivation, but the pathway by which they can maintain the metabolite levels to meet their high energy demands is not fully understood (26). Furthermore, studies examining metabolic flux in the retina indicate the need for energy homeostasis across the photoreceptor cell layer and with the RPE to maintain retinal health and visual acuity (27)(28)(29)(30). Therefore, the mitochondria arrangement described in this study may be an important evolutionary development for sharing the level of particular metabolites across the photoreceptor cell layer.…”

Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, provides photoreceptor neuroprotection

“…21–24 PKM2 is expressed by photoreceptors in the retina while PKM1 expression is confined to the inner retina, and ML-265 shows a high degree of selectivity for PKM2 over other isoforms, PKM1, PKR, and PKL. 5,10,12,13,15,17,20–22 Therefore, ML-265 represents an ideal lead molecule to explore the neuroprotective effects of pharmacologically activating PKM2 in photoreceptors. In line with previous reports, ML-265 displayed potent activation of recombinant human PKM2 with a maximum activation of 249 ± 14% (best-fit value ± std.…”

“…We recently reported that a key regulator of aerobic glycolysis, PKM2, plays a critical function in photoreceptor survival during acute outer retinal stress. 15 PKM2 converts phosphoenolpyruvate (PEP) and adenosine diphosphate (ADP) to pyruvate and ATP in the final rate-limiting step of glycolysis. Photoreceptors maintain expression of PKM2 after differentiation, unlike other neurons, which exclusively express the constitutively active PKM1 isoform following terminal differentation.…”

“…Photoreceptors maintain expression of PKM2 after differentiation, unlike other neurons, which exclusively express the constitutively active PKM1 isoform following terminal differentation. 5,13,15–17 PKM2 activity is tightly regulated whereas PKM1 is constitutively active. 8 As a tetramer, PKM2 displays high catalytic activity and is associated with increased ATP synthesis and catabolic metabolism.…”

“…PKM2 localizes primarily to the outer retina while PKM1 expression is mostly confined to the inner retina. 12,15,20 The loss of Pkm2 in photoreceptors led to the compensatory expression of Pkm1 and upregulation of genes involved in glucose metabolism. When these animals were subjected to acute outer retinal stress produced by experimental retinal detachment, they displayed decreased photoreceptor apoptosis and improved survival.…”