Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world, with an increasing financial burden on the entire population. The dry form of AMD is characterized by the death of the retinal pigment epithelium (RPE). Numerous studies have implicated mitochondrial dysfunction as a potential part of AMD pathology. Mitochondrial damage and dysfunction have been found in both RPE tissue and primary RPE cultures from human donors with AMD. A bioenergetic crisis due to mitochondrial dysfunction could lead to the multiple phenotypes associated with AMD, including inflammation and cell death. Mitochondrial homeostasis, including biogenesis, fusion, fission, and mitochondrial autophagy (mitophagy), is a prime target for therapies. However the pathway that leads to the accumulation of dysfunctional and damaged mitochondria in AMD is not known. The three specific aims will assess mitochondrial biogenesis, fusion, and fission (Aim 1), mitophagy (Aim 2), and potential molecular mechanisms (Aim 3) primarily using mitochondrial-targeted fluorescent probes to measure these dynamic processes. Pharmacological activators or inhibitors will be used to assess the effect of mitochondrial homeostasis on mitochondrial function. Preliminary data support the feasibility of using different mitochondrial targeted fluorescent proteins to measure mitochondrial homeostasis. Identifying the step of mitochondrial homeostasis responsible for accumulation of damaged mitochondria will provide therapeutic targets to treat AMD.
Among the current hypotheses defining the mechanism behind AMD is that a bioenergetic crisis, stemming from RPE mitochondrial dysfunction, drives disease pathology. This F31 proposal will examine pathways of mitochondrial homeostasis (biogenesis, fusion, fission, and mitophagy) to identify the site of defect and determine the effect on RPE mitochondrial function. Results from this study will provide insight into AMD pathobiology and identify potential therapeutic targets.