Recent Advances in Our Understanding of Age-Related Macular Degeneration: Mitochondrial Dysfunction, Redox Signaling, and the Complement System

Abstract

Age-related macular degeneration (AMD) is a prevalent degenerative disorder of the central retina, which holds global significance as the fourth leading cause of blindness. The condition is characterized by a multifaceted pathophysiology that involves aging, oxidative stress, inflammation, vascular dysfunction, and complement activation. The complex interplay of these factors contributes to the initiation and progression of AMD. Current treatments primarily address choroidal neovascularization (CNV) in neovascular AMD. However, the approval of novel drug therapies for the atrophic and more gradual variant, known as geographic atrophy (GA), has recently occurred. In light of the substantial impact of AMD on affected individuals' quality of life and the strain it places on healthcare systems, there is a pressing need for innovative medications. This paper aims to provide an updated and comprehensive overview of advancements in our understanding of the etiopathogenesis of AMD. Special attention will be given to the influence of aging and altered redox status on mitochondrial dynamics, cell death pathways, and the intricate interplay between oxidative stress and the complement system, specifically in the context of GA. Additionally, this review will shed light on newly approved therapies and explore emerging alternative treatment strategies in the field. The objective is to contribute to the ongoing dialogue surrounding AMD, offering insights into the latest developments that may pave the way for more effective management and intervention approaches.

Figure 1.

The multifaceted nature of age-related macular degeneration involves crucial etiopathogenetic factors, including light exposure, aging, tobacco smoking, and genetics. These factors intricately intertwine, collectively giving rise to pathophysiological changes in the retinal pigment epithelium (RPE) and photoreceptors. This complex interplay manifests through events such as oxidative stress, mitochondrial dysfunction, inflammatory processes, generation of retinal autoantibodies, and aberrant complement activation, ultimately triggering various programmed cell death pathways. The onset of the disease typically becomes apparent in its late manifestation, presenting in two primary forms. The first, geographic atrophy, is the most prevalent variant, characterized by a slow progression and primarily associated with the loss of photoreceptors and RPE cells. The second, choroidal neovascularization, represents a more aggressive variant marked by neoangiogenesis, hemorrhages, and edemas.

Figure 2.

Fundus autofluorescence, fluorescein angiography photographs, and horizontal OCT scans over the fovea depict examples of geographic atrophy (GA) (A-D) and neovascular age-related macular degeneration (AMD) (E and F). In panel (A), a fundus autofluorescence image from a patient with geographic atrophy is presented. The white arrow indicates the atrophic area characterized by a significant reduction in fundus autofluorescence due to the absence of retinal pigment epithelial (RPE) cells, resulting in the absence of autofluorescent lipofuscin. The white arrowheads highlight spots of increased autofluorescence attributed to lipofuscin accumulation and drusen surrounding the atrophic area. (B) Utilizing high-resolution spectral-domain OCT (SD-OCT), the image reveals significant thinning of the RPE (indicated by the white arrow) and the loss of the overlying outer retinal layers within the atrophic area. (C) In fluorescein angiography, atrophic patches manifest as clearly defined, brightly fluorescent areas. This occurs due to heightened visibility of the underlying choroidal fluorescence resulting from the absence of RPE cells. Normally, these cells would attenuate fluorescein transmission. (D) With SD-OCT, an irregular appearance of the RPE band with dome-shaped elevations of the RPE corresponding to drusen (white arrow), RPE thinning (white arrowhead), and loss of outer retinal layers is seen. (E) Fluorescein angiogram illustrating a classic choroidal neovascularization (CNV) characterized by abnormal leakage in regions of choroidal neovascular membranes. (F) The OCT scan shows an elevated and disrupted RPE, hyperreflective material (white arrows) below and above the RPE, as well as sub-and intraretinal fluid (white arrowheads).

Figure 3.

Illustration on risk determinants and presentation in AMD. CF: complement factor; ROS: reactive oxygen species; RPE: retinal pigment epithelium; AMD: age-related macular degeneration; ARMS2: age-related maculopathy susceptibility 2 gene; HTRA1: high-temperature requirement A serine peptidase 1 gene; ApoE: apolipoprotein E; BM: Bruch’s membrane; GA: geographic atrophy; CNV: choroidal neovascularization.

Figure 4.

Overview of the different cell death pathways in AMD-RPE. RPE: retinal pigment epithelium; IL: interleukin; MLKL: mixed lineage kinase domain-like pseudokinase; RIPK: receptor interacting protein kinase; TNF-α: tumor necrosis factor alpha; TNFR: tumor necrosis alpha receptor; TLR: toll-like receptor; LPS: lipopolysaccharide; DAMP: damage-associated molecular patterns; PAMP: pathogen-associated molecular patterns; NLRP 3: NOD-like receptor, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3; ASC: adapter protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; GSDMD: gasdermin D; NF-kB: nuclear factor 'kappa-light-chain-enhancer' of activated B-cells; ROS: reactive oxygen species; JAK: Janus kinase; STAT: signal transducers and activators of transcription; INF-γ: interferon gamma; GSH: glutathione.

Figure 5.

Triggers of structural changes in the RPE and morphological characteristics of healthy and AMD-RPE. RPE: retinal pigment epithelium; AMD: age-related macular degeneration; BM: Bruch’s membrane; mtDNA: mitochondrial DNA.

Figure 6.

Interrelation between oxidative stress, complement activation and generation of autoantibodies in AMD. CF: complement factor; MBL: mannose-binding lectin; MCP: membrane cofactor protein; DAF: decay-accelerating factor; TLR: toll-like receptor; ROS: reactive oxygen species; MDA: malonyldialdehyde.