Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration

Abstract

Photoreceptors are the most numerous and metabolically demanding cells in the retina. Their primary nutrient source is the choriocapillaris, and both the choriocapillaris and photoreceptors require trophic and functional support from retinal pigment epithelium (RPE) cells. Defects in RPE, photoreceptors, and the choriocapillaris are characteristic of age-related macular degeneration (AMD), a common vision-threatening disease. RPE dysfunction or death is a primary event in AMD, but the combination(s) of cellular stresses that affect the function and survival of RPE are incompletely understood. Here, using mouse models in which hypoxia can be genetically triggered in RPE, we show that hypoxia-induced metabolic stress alone leads to photoreceptor atrophy. Glucose and lipid metabolism are radically altered in hypoxic RPE cells; these changes impact nutrient availability for the sensory retina and promote progressive photoreceptor degeneration. Understanding the molecular pathways that control these responses may provide important clues about AMD pathogenesis and inform future therapies.

DOI: http://dx.doi.org/10.7554/eLife.14319.001

eLife digest

Cells use a sugar called glucose as fuel to provide energy for many essential processes. The light-sensing cells in the eye, known as photoreceptors, need tremendous amounts of glucose, which they receive from the blood with the help of neighboring cells called retinal pigment epithelium (RPE) cells. Without a reliable supply of this sugar, the photoreceptors die and vision is lost.

As we age, we are at greater risk of vision loss because RPE cells become less efficient at transporting glucose and our blood vessels shrink so that the photoreceptors may become starved of glucose. To prevent age-related vision loss, we need new strategies to keep blood vessels and RPE cells healthy. However, it was not clear exactly how RPE cells supply photoreceptors with glucose, and what happens when blood supplies are reduced.

To address this question, Kurihara, Westenskow et al. used genetically modified mice to investigate how cells in the eye respond to starvation. The experiments show that when nutrients are scarce the RPE cells essentially panic, radically change their diet, and become greedy. That is to say that they double in size and begin burning fuel faster while also stockpiling extra sugar and fat for later use. In turn, the photoreceptors don’t get the energy they need and so they slowly stop working and die.

Kurihara, Westenskow et al. also show that there is a rapid change in the way in which sugar and fat are processed in the eye during starvation. Learning how to prevent these changes in patients with age-related vision loss could protect their photoreceptors from starvation and death. The next step following on from this research is to design drugs to improve the supply of glucose and nutrients to the photoreceptors by repairing aging blood vessels and/or preventing RPE cells from stockpiling glucose for themselves.

DOI: http://dx.doi.org/10.7554/eLife.14319.002