Mitochondria in Retinal Ganglion Cells: Unraveling the Metabolic Nexus and Oxidative Stress

Abstract

This review explored the role of mitochondria in retinal ganglion cells (RGCs), which are essential for visual processing. Mitochondrial dysfunction is a key factor in the pathogenesis of various vision-related disorders, including glaucoma, hereditary optic neuropathy, and age-related macular degeneration. This review highlighted the critical role of mitochondria in RGCs, which provide metabolic support, regulate cellular health, and respond to cellular stress while also producing reactive oxygen species (ROS) that can damage cellular components. Maintaining mitochondrial function is essential for meeting RGCs' high metabolic demands and ensuring redox homeostasis, which is crucial for their proper function and visual health. Oxidative stress, exacerbated by factors like elevated intraocular pressure and environmental factors, contributes to diseases such as glaucoma and age-related vision loss by triggering cellular damage pathways. Strategies targeting mitochondrial function or bolstering antioxidant defenses include mitochondrial-based therapies, gene therapies, and mitochondrial transplantation. These advances can offer potential strategies for addressing mitochondrial dysfunction in the retina, with implications that extend beyond ocular diseases.

Keywords: antioxidants; autosomal dominant optic atrophy; gene therapy; glaucoma; metabolism; mitochondria; mitochondrial transplantation; oxidative stress; retinal ganglion cells; retinopathy.

Figure 1

The Cytoarchitecture of Retinal Ganglion Cells Contributing to High Metabolic Demands. IPL, inner plexiform layer; GCL, ganglion cell layer; NFL, nerve fiber layer.

Figure 2

Representative section of a retina from a mito:mKate2 mouse (JAX #032188). This image displays mitochondria expressing far-red fluorescence due to the mKate2 protein, which is fused to the N-terminal of the cytochrome c oxidase subunit VIII, targeting it specifically toward mitochondria (shown in red). Nuclei are labeled with DAPI staining (blue). RGC: retinal ganglion cell; IPL: inner plexiform layer; INL: inner nuclear layer; OPL: outer plexiform layer; ONL: outer nuclear layer; IS: inner segment; OS: outer segment. RPE: retinal pigment epithelium.

Figure 3

The Genetic and Molecular Pathways of Mitochondrial Dysfunction in Hereditary Optic Neuropathies. OMM, outer mitochondrial membrane. IMM, inner mitochondrial membrane; TCA, tricarboxylic acid cycle; NADH, nicotinamide adenine dinucleotide; FADH₂, flavin adenine dinucleotide; ATP: adenosine triphosphate; OPA, optic atrophy; CMT, Charcot-Marie-Tooth Disease; LHON, Leber’s hereditary optic neuropathy; mtDNA, mitochondrial DNA; OMA1, M-AAA protease; MICOS, mitochondrial contact site and cristae organizing system.

Figure 4

Schematic of Reactive Oxygen Species (ROS) Metabolism and Antioxidant Defense Pathway. ROS are represented by maroon text boxes, whereas antioxidants are presented in turquoise text boxes. O₂: molecular oxygen; O₂^•−: superoxide anion radicals; H₂O₂: hydrogen peroxide; HO^•: hydroxyl radicals; HOCl: hypochlorous acid; H₂O: hydrogen oxide, water; ROOH: organic hydroperoxide; MDA: malondialdehyde; 4-HNE: 4-hydroxynonenal; PUFA: polyunsaturated fatty acid; NOS: nitric oxide synthase; NO^•: nitric oxide; ONOO⁻: peroxynitrite; SOD: superoxide dismutase; G6PD: glucose 6-phosphate dehydrogenase; GSH: glutathione; GSSH: oxidized glutathione; NADPH: nicotinamide adenine dinucleotide phosphate; TRX: thioredoxin.