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

Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium

“…A recent report showed that RPE is less stable and less able to support the retina when it is forced to rely on glycolytic rather than mitochondrial metabolism (13). Another recent report supports the importance of mitochondria in RPE by showing that bolstering mitochondrial activity makes these cells more resilient to oxidative damage (14).…”

“…Comparison of M5 citrate and M5 αKG in cells and tissues incubated with 13 C-glutamine shows that reductive carboxylation is more active in RPE than in other cells and tissues (Fig. S2D).…”

“…Both malic enzyme activity (formation of M3 pyruvate from U-13 C glutamine) (Fig. S2B) and pentose phosphate pathway (PPP) activity [formation of M1 pyruvate from 1,2 13 C-glucose (28)] (Fig. S2C) are minor compared with reductive carboxylation in hfRPE cells.…”

“…Using 13 C metabolic flux analysis in human RPE cells, we found that RPE has an exceptionally high capacity for reductive carboxylation, a metabolic pathway that has recently garnered significant interest because of its role in cancer cell survival. The capacity for reductive carboxylation in RPE exceeds that of all other cells tested, including retina, neural tissue, glial cells, and a cancer cell line.…”

Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa

“…In RP, mutations in genes encoding phototransduction enzymes such as rhodopsin and phosphodiesterase 6 (PDE6) impair photoexcitation, creating imbalance between anabolic and catabolic processes that leads to shortening of the outer segments (OS) of photoreceptors and eventually triggering cell death (2,(9)(10)(11)(12). The OS is shed and regenerated daily, but in diseased photoreceptors, there are aberrations in the renewal cycle that lead to significantly shorter OS and subsequent dysgenesis (2,9).…”