Perspective on AMD Pathobiology: A Bioenergetic Crisis in the RPE

Abstract

AMD is the leading cause of blindness in developed countries. The dry form of AMD, also known as atrophic AMD, is characterized by the death of RPE and photoreceptors. Currently, there are no treatments for this form of the disease due in part to our incomplete understanding of the mechanism causing AMD. Strong experimental evidence from studies of human donors with AMD supports the emerging hypothesis that defects in RPE mitochondria drive AMD pathology. These studies, using different experimental methods, have shown disrupted RPE mitochondrial architecture and decreased mitochondrial number and mass, altered content of multiple mitochondrial proteins, increased mitochondrial DNA damage that correlates with disease severity, and defects in bioenergetics for primary RPE cultures from AMD donors. Herein, we discuss a model of metabolic uncoupling that alters bioenergetics in the diseased retina and drives AMD pathology. These data provide the rationale for targeting the mitochondria in the RPE as the most efficacious intervention strategy if administered early, before vision loss and cell death.

Figure 1

Mitochondria as a signaling platform. The mitochondria contribute to a number of cellular functions, including energy production, regulation of intracellular calcium levels, and production of ROS, all of which contribute to anterograde and retrograde signaling. Excessive ROS can damage mtDNA, proteins, and lipids. Damage to the mitochondrial genome can produce defective proteins of the ETC and translation machinery. ROS can also directly damage mitochondrial proteins, including those in the respiratory chain, thereby adversely affecting energy production. Mitochondrial membrane damage can lead to opening of mitochondrial permeability transition pores, decreasing membrane potential, and releasing mtDNA, and the proteins apoptosis-inducing factor and cytochrome c. Release of these mitochondrial molecules initiates cell death via apoptosis and activates the inflammasome, potentially leading to pyroptosis or necroptosis.

Figure 2

Bioenergetics of the retinal ecosystem. In a healthy retina (left), glucose (Glu) from the choroid remains unused by the RPE and is shuttled to the photoreceptors (PRs). PRs use glucose in glycolysis to produce ATP and the by-product lactate (Lac). Lactate is taken up by the RPE, converted to pyruvate (Pyr), and used in OxPhos. PRs also supply RPE with an influx of lipids through phagocytosis of the outer segments and degradation on fusion with the lysosome (L). These lipids enter the mitochondria and are used in β-oxidation (β-Ox) to generate ATP. In AMD (right), the RPE's damaged mitochondria lose the ability to generate ATP, causing the cell to use Glu from the choroid, due to its new reliance on glycolysis. This lowers the concentration of Glu transported to the PRs, and consequently lowering lactate supplied to the RPE. This cell-specific shift in reliance on alternative bioenergetics upsets the metabolic ecosystem and leads to death of both PRs and RPE. Thus, metabolic uncoupling that alters retinal bioenergetics may be the central defect in AMD. Adapted from Kanow et al.