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Douglas Vollrath, Melissa Calton; Rebalancing RPE energy metabolism slows retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3024.
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© ARVO (1962-2015); The Authors (2016-present)
We previously showed that postnatal loss of RPE oxidative phosphorylation (OXPHOS) in the murine RPE triggers increased aerobic glycolysis, mTOR-mediated dedifferentiation, lipid accumulation and photoreceptor degeneration, supporting a causal role for degradation of RPE OXPHOS in the pathogenesis of age-related macular degeneration (AMD). We next sought to determine whether an imbalance between RPE OXPHOS and aerobic glycolysis, rather than OXPHOS ablation per se, can cause the observed retinal abnormalities. To do so, we assessed the in vivo consequences of enhancing murine RPE aerobic glycolysis in the presence of intact OXPHOS machinery, and subsequently rebalancing metabolism through stimulation of OXPHOS.
We created mice with postnatal RPE-selective ablation of prolyl-hydroxylase (PHD) genes 1-3 (i.e. Egln1-3) to stabilize hypoxia inducible factor (HIF) and enhance aerobic glycolysis. Retinas of mutant mice and controls were studied at various ages by histology, immunofluorescence, immunoblot, qRT-PCR, funduscopy, electroretinography (ERG), ocular coherence tomography, and ex vivo extracellular flux analysis. Animals were treated by daily intraperitoneal injection of dichloroacetate and oxamate (DO) to stimulate OXPHOS.
The retinas of mutant mice develop normally, but the RPE is histologically abnormal as early as postnatal day 17. The RPE eventually exhibits increased aerobic glycolysis, mTOR activation, hypertrophy, glycogen accumulation, altered pigmentation, and loss of polarity, integrity and characteristic markers, but shows no evidence of increased lipids or induction of VEGF. Levels of HIF-1, but not HIF-2, are increased. ERG amplitudes are depressed and photoreceptors progressively die. DO treatment stimulates OXPHOS in mutant eyecups, and in vivo improves RPE integrity, preserves ERG amplitudes, and slows the loss of photoreceptors, while not altering mTOR activation or the levels of selected RPE markers.
Our results suggest that increased RPE aerobic glycolysis causes RPE and, indirectly, photoreceptor dysfunction in response to stabilization of HIF-1, a protein that could plausibly be activated during AMD pathogenesis. Increasing OXPHOS in a glycolytic milieu mitigates the loss of RPE integrity, and partially preserves photoreceptor function and numbers. Thus, the RPE aerobic glycolysis/OXPHOS balance is critical for retinal homeostasis.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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