Fig. 3: Processes involved in cell homeostasis and cell death.

a Proteostasis describes the regulation of protein levels and their regulated degradation and is of primary importance in cells. Energy homeostasis and mitophagy are critical processes as the outer retina is the most energy-/ATP-requiring tissue in the body. ECM homeostasis describes the finely tuned processes of production and degradation of ECM components that are essential to ensure the mechanical homeostasis of tissues. Dysfunctional and failed cell–ECM contacts can cause cell death through anoikis. Autophagy is a critical cell homeostatic process that removes nonfunctional, redundant cilia that are too long, as well as aggregated proteins or organelles via the lysosomal machinery. However, autophagy may also cause cell death (autosis) under certain conditions. Cholesterol homeostasis is a critical process as the amount of membrane needed for the genesis of the outer disks is immense. Parainflammation describes the basal immune activation that the retina has because of its immune privilege, where under normal conditions microglia, perivascular macrophages, dendritic cells, and the complement system are basally activated in response to day to day damage and contribute to retinal homeostasis. Antioxidants are critical as ROS are generated from both internal (e.g., resulting from mitochondrial metabolism, outer segment phagocytosis, and NADPH oxidases) and external sources (e.g., light, smoking and high glucose) sources. Outer segment phagocytosis (heterophagy) and degradation of intracellular components (autophagy) requires lysosomal-mediated waste clearance. Choroidal vascular homeostasis and choroidal circulation are indispensable for mass exchange (nutrients, oxygen, etc.) with the outer retina. Hypoxia and associated metabolic stress in RPE cells can cause PR cell death. Dysfunctional lipid homeostasis can cause apoptosis, necroptosis, or ferroptosis. b Functional classes for the 110 AMD-risk proteins in the quantitative binary AMD network. The function for each risk protein was manually analyzed be detailed literature analyses and, if possible it was assigned to one of the 10 homeostasis functions or to one of the 7 modes of cell death. If this was not possible, it was assigned to other functional categories, such as transcription, general signaling, cytoskeleton, retinoic cycle, etc.