Complement activation, lipid metabolism, and mitochondrial injury: Converging pathways in age-related macular degeneration

Abstract

The retinal pigment epithelium (RPE) is the primary site of injury in non-neovascular age-related macular degeneration or dry AMD. Polymorphisms in genes that regulate complement activation and cholesterol metabolism are strongly associated with AMD, but the biology underlying disease-associated variants is not well understood. Here, we highlight recent studies that have used molecular, biochemical, and live-cell imaging methods to elucidate mechanisms by which aging-associated insults conspire with AMD genetic risk variants to tip the balance towards disease. We discuss how critical functions including lipid metabolism, autophagy, complement regulation, and mitochondrial dynamics are compromised in the RPE, and how a deeper understanding of these mechanisms has helped identify promising therapeutic targets to preserve RPE homeostasis in AMD.

Cell-autonomous lipid-handling defects in Stargardt iPSC-derived retinal pigment epithelium cells

“…It is, however, not clear if, in STGD1-iRPE, phagolysosomal dysfunction is primarily caused by ABCA4 LOF or indirectly by ceramide accumulation, as has been suggested previously ( Kaur et al., 2018 ). In the RPE, excess ceramide alters membrane dynamics and results in aberrant endosome biogenesis, impaired autophagosome trafficking, and mitochondrial fragmentation ( Kaur et al., 2018 ; Tan et al., 2020 ). In addition, ceramide’s role in phagolysosomal maturation was shown previously ( Pathak et al., 2018 ).…”

Pathophysiology of Age-Related Macular Degeneration: Implications for Treatment

“…In humans, increased ceramide levels in the serum and RPE have been reported in patients with AMD but not in unaffected controls. Recent studies have suggested that bis-retinoids lead to a secondary accumula-tion of cholesterol and ceramide due to a biophysical interaction between these lipids [34].…”

Human pluripotent stem cells for the modelling of retinal pigment epithelium homeostasis and disease: A review

“…The RPE lines the back of the retina as a layer of pigmented, post-mitotic and polygonal cells. 2 The RPE has many fundamental functions that ensure the homeostasis and functioning of the retina, including: phagocytosis of shed photoreceptor outer segments, secretion of proteins for paracrine cellular communication, active transport of biomolecules, ion homeostasis, isomerization of all-transretinol to 11-cis retinal, and light absorption in melanosomes. Although not sensory cells themselves, the RPE cells are involved in intimate bioprocessing with photoreceptors, providing a critical role in their structural and functional viability.…”