Abstract
Mitochondria are central in retinal cell function and survival and they perform functions that are critical to cell function. Retinal neurons have high energy requirements, since large amounts of ATP are needed to generate membrane potentials and power membrane pumps. Mitochondria over the course of aging undergo a number of changes. Aged mitochondria exhibit decreased rates of oxidative phosphorylation, increased reactive oxygen species (ROS) generation and increased numbers of mtDNA mutations. Mitochondria in the neural retina and the retinal pigment epithelium are particularly susceptible to oxidative damage with aging. Many age-related retinal diseases, including glaucoma and age-related macular degeneration, have been associated with mitochondrial dysfunction. Therefore, mitochondria are a promising therapeutic target for the treatment of retinal disease.
1. Retinal Anatomy and Physiology
The fundamental organization of the retina is conserved across vertebrates. The retina contains five major neuronal cell classes (photoreceptors, bipolar cells, amacrine cells, horizontal cells, and retinal ganglion cells) with Müller glial cells and retinal pigment epithelial cells providing metabolic and homeostatic support [1] (Figure 1). The interaction of light with light-sensitive pigments in the outer segments of rod and cone photoreceptors initiates signaling mechanisms that convert light energy to neural activity. Photoreceptors synapse with bipolar cells. Bipolar cells synapse with the retinal ganglion cells that transmit the visual signal along their axons (optic nerve) and, ultimately, to the brain. The retinal pigment epithelium envelopes the photoreceptors, which facilitates the diffusion of nutrients, key metabolites, and oxygen from the choroidal vessels. Horizontal cells, amacrine cells, and Muller cells mediate and support the synapses between the retinal neurons. Unique to the Muller cell, its processes span the inner retina and most of the outer retina, assisting in the maintenance of multiple synapses throughout the retina. Pericytes surround the vascular endothelial cells in all retinal layers, forming the blood-retinal barrier.
2. Mitochondrial Dysfunction with Aging and Disease
2.1. Age-Related Mitochondrial Changes
Mitochondria are central to retinal cell function and survival and they perform a variety of functions critical to cell metabolism, including oxidative phosphorylation, beta-oxidation of fatty acids, calcium homeostasis, and the regulation of neuronal excitability [7,8,9,10,11,12,13]. Retinal neurons have high energy requirements and large amounts of ATP are needed to generate membrane potentials and power membrane pumps. It has been estimated that 90% of mitochondria-generated ATP is used to maintain transmembrane ion gradients [10].
Mitochondria in the aging retina show a decline in the function of the electron transport chain and a significant increase in the generation of reactive oxygen species (ROS) (Figure 2). This increased ROS production leads to increased oxidative damage to mitochondrial DNA, lipids, and proteins [5,6,14,15,16]. With aging, there is an accumulation of mtDNA mutations and a disruption of mitochondrial structure. Mitochondrial genomic instability has been postulated to play an important role in age-related retinal pathophysiology [16]. However, murine studies have shown that the majority of mtDNA mutations in aged cells appear to be caused by replication errors early in life, rather than by oxidative damage [15]. Mitochondrial DNA repair pathways are limited and they begin to fail with aging, leading to additional mtDNA damage and contributing to the development of retinal degenerative diseases [8,9].
2.2. Age-Related Macular Degeneration
Age-related macular degeneration (AMD) is the leading cause of blindness in individuals over 65 in developed countries [17]. As the name implies, AMD primarily affects the central retina or macula. It is characterized by the development of drusen, extracellular lipoprotein deposits under the retinal pigment epithelium (RPE), in the early stages of the disease, followed by the loss of photoreceptors and RPE. Choroidal neovascularization (CNV) develops during later stages of the disease (wet AMD) [17]. Choroidal neovascularization (CNV) is the growth of new blood vessels that originate from the choroid through a break in Bruch’s membrane into the subretinal space or sub-retinal pigment epithelium. Dry or atrophic AMD is the most common form of AMD and there are no treatments for this form of AMD.
Aging is a recognized factor that is associated with mitochondrial dysfunction in the outer retina. Other important risk factors for the development of AMD are genetics and environmental stressors, including smoking and exposure to ultraviolet and blue light [18,19,20,21,22,23,24]. All of these factors are likely to result in mtDNA damage in the RPE.
Recent studies suggest that a bioenergetic crisis in the RPE contributes to the pathology of AMD, as illustrated in Figure 3 [20]. Analysis of retinal tissue from human donors with AMD have documented a reduction in the mitochondrial number, a disruption in mitochondrial structure and an increase in mtDNA damage in the RPE that correlates with the severity of disease [15,16,17,18]. Recent studies in the primary cultures of RPE derived from human donors with and without AMD have shown decreased rates of ATP synthesis from oxidative phosphorylation and glycolysis in AMD donors consistent with a bioenergetic crisis. Fisher and Ferrington (2018) have suggested that mitochondrial damage is limited to the RPE, because these cells rely nearly exclusively on mitochondrial oxidative phosphorylation, whereas photoreceptors utilize aerobic glycolysis [4,5,6,7]. In addition to disruptions in mitochondrial bioenergetics, mitochondrial dysfunction has been shown to disrupt calcium homeostasis and mitochondrial nuclear signaling. Several studies have suggested that therapeutic approaches that target RPE mitochondria may provide an effective early treatment strategy for AMD [18,19,20,21,22].
