Metabolism Dysregulation in Retinal Diseases and Related Therapies

Abstract

The human retina, which is part of the central nervous system, has exceptionally high energy demands that requires an efficient metabolism of glucose, lipids, and amino acids. Dysregulation of retinal metabolism disrupts local energy supply and redox balance, contributing to the pathogenesis of diverse retinal diseases, including age-related macular degeneration, diabetic retinopathy, inherited retinal degenerations, and Macular Telangiectasia. A better understanding of the contribution of dysregulated metabolism to retinal diseases may provide better therapeutic targets than we currently have.

Identification of Novel Pathways Regulated by APE1/Ref-1 in Human Retinal Endothelial Cells

“…A recent publication demonstrated that APEX1 KD in PDAC cells downregulated genes involved in metabolic pathways, including glycolysis, suggesting a universal function of APE1 in regulating glycolysis [ 38 ]. Glucose homeostasis is regulated by glycolysis, the TCA cycle, and OXPHOS, and dysregulation of glucose homeostasis contributes to the pathogenesis of blinding NV eye diseases such as diabetic retinopathy (DR) and AMD [ 39 ]. In the retina, glycolysis is essential for endothelial cell (EC) proliferation, as the retina metabolizes most glucose through anaerobic glycolysis to promote the rapid production of ATP with faster kinetics and produce lactate and other intermediates necessary for proliferating cells to generate amino acids, lipids, and nucleotides [ 40 , 41 , 42 ].…”

“…ECs rely on glycolysis instead of OXPHOS to produce ATP during angiogenesis, even in the presence of oxygen [ 41 , 43 , 44 , 45 , 46 ]. This metabolic alteration, known as the Warburg effect, is also utilized by cancer cells to allow for their proliferation [ 39 , 47 ]. ScRNA-seq revealed that angiogenic ECs become enriched in glycolysis genes compared to quiescent ECs [ 41 , 48 ].…”

“…Proper cell division for proliferation requires an adequate supply of nucleotides for DNA and RNA synthesis. These nucleotides can be produced by leveraging amino acids and other small molecules to build purine and pyrimidine rings [ 39 , 47 ]. Purine metabolism is implicated in several NV eye diseases, and previous work has identified aberrant purine metabolites in the plasma of DR patients, indicating dysfunctional purine metabolism during disease to support EC proliferation [ 60 , 61 ].…”

Metabolic Characterization of Ocular Tissues in Relation to Laser-Induced Choroidal Neovascularization in Rats

“…It has been proven that purine has an important physiological function and is involved in intercellular energy metabolism. 30 Purine metabolism is also involved in intracellular energy metabolism and may be used as an alternative pathway to overcome insufficient glucose supply and energy crisis during neurodegeneration. 31 In addition, purine metabolism can affect multiple cellular functions by activating intercellular communication through receptors.…”

“…Remarkably, purine metabolism was the most significantly altered pathway in the RPE/choroid. It has been proven that purine has an important physiological function and is involved in intercellular energy metabolism . Purine metabolism is also involved in intracellular energy metabolism and may be used as an alternative pathway to overcome insufficient glucose supply and energy crisis during neurodegeneration .…”