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Melissa Ann Calton, Douglas Vollrath; Alteration of retinal pigment epithelium metabolism mediates retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5520.
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Increased prevalence of retinal pigment epithelium (RPE) mitochondrial DNA mutations is associated with age-related macular degeneration. Prior work from our lab showed that RPE-selective loss of mitochondrial oxidative phosphorylation (OXPHOS) in mice leads to increased aerobic glycolysis and mTOR-mediated RPE dedifferentiation. We hypothesize that both RPE OXPHOS and aerobic glycolysis are necessary for cell function, and that the balance between these two metabolic modes is critical for retinal homeostasis.
To investigate the role of RPE increased glycolysis in mediating retinal degeneration, we genetically stabilized HIF-1α in an RPE-selective manner in mice to enhance aerobic glycolysis in the context of a competent OXPHOS system. We assessed retinal structure and integrity by funduscopy, optical coherence tomography, and histology, and evaluated retinal function by electroretinography (ERG). We assessed RPE molecular characteristics by performing qRT-PCR, immunoblotting and immunofluorescence to evaluate epithelial attributes, cellular morphology, mTOR activation and the expression levels of RPE-characteristic proteins and genes.
Postnatal augmentation of glycolysis in the RPE leads to loss of epithelial attributes as early as six weeks of age and progressing in severity with age. The RPE of mutant mice is hypertrophic, has lost pigmentation, and exhibits mTOR activation. HIF-1α stabilization causes decreased expression of Sox9 mRNA and RPE-characteristic proteins, and increased expression of the RPE cell fate determinant MITF, indicating RPE dedifferentiation. The loss of RPE integrity results in drastically decreased retinal function compared to littermate controls. Mutant mice have grossly abnormal fundi, decreased outer nuclear layer thicknesses, and reduced ERG scotopic and photopic amplitudes, together indicative of photoreceptor degeneration.
In vivo augmentation of RPE glycolysis causes rapid degradation of epithelial integrity with evidence of mTOR activation and RPE dedifferentiation, ultimately resulting in photoreceptor degeneration. Together with previous reports, these data suggest that the aging RPE undergoes a shift toward diminished OXPHOS capacity and increased glycolysis, leading to RPE dysfunction and loss of retinal integrity. Inhibiting glycolysis or stimulating OXPHOS may therefore be an attractive therapy for certain retinal degenerative diseases.
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