Our laboratory studies how intracellular defense systems cooperate to protect cells against oxidative and proteotoxic stress. The three systems we focus on are: (1) the ubiquitin proteolytic system (UPS), (2) the Nrf2 anti-oxidant system, and (3) the mitochondrial network. Each of these undergoes age-dependent deficits and has been linked to the onset and progression of age-related macular degeneration (AMD), the disease of interest in our laboratory. AMD is the leading cause of irreversible vision loss among the elderly yet no reliable therapies exist for dry AMD (dAMD), the most prevalent form of the disease. Much of our work focuses on the retinal pigment epithelium (RPE), a single layer of cells posterior to the retina that provides trophic support to the light-sensing photoreceptors. The functions and anatomical position of the RPE subject it to chronic oxidative and proteotoxic stress. As a result, RPE dysfunction and atrophy precipitate photoreceptor loss in many cases of dAMD. Our recent tissue culture RPE cell findings combined with our newly-developed RPE-specific knockout mouse models have positioned us to test the hypothesis that concomitant failure of the UPS and Nrf2 anti-oxidant systems culminates in a chronic state of stress that overwhelms mitochondrial dynamics (i.e., fusion and fission). The resulting accumulation of damaged mitochondria in turn drives RPE cells towards apoptosis, ultimately inducing dAMD onset.