Purpose Retinal pigment epithelium (RPE) cell dysfunction and death are hypothesized to play central roles in age-related macular degeneration (AMD), and reduction of RPE mitochondrial function also has been implicated in the pathogenesis of AMD. We sought to create a model of postnatal RPE degeneration due to loss of mitochondrial function and gain insight into the RPE response to respiratory chain deficiency and the resulting consequences for neighboring cells.

Methods We generated mice homozygous for Tfam^loxp, a conditional null allele of a nuclear gene essential for mitochondrial function, and heterozygous for a cre recombinase transgene driven by a fragment of the human BEST1 promoter (Tfam^loxp/Tfam^loxp, +/BEST1-cre), which should restrict ocular loss of mitochondrial function to the postnatal RPE. We characterized the histological and molecular changes in the RPE following loss of mitochondrial function, particularly the loss of oxidative phophorylation (OXPHOS).

Results The mice display severe mitochondrial dysfunction resulted from loss of OXPHOS in 90% of RPE cells (cre-expressing cells) at 9 weeks of age. The retinas of these mice initially appear completely normal, with little evidence of RPE apoptosis at any age tested, as old as one year. Instead, the epithelium gradually undergoes dedifferentiation typified by reduction of RPE-characteristic proteins, cellular hypertrophy, loss of cell polarization and adhesion, abnormal RPE cell proliferation, migration of RPE cells into the photoreceptor layer, autofluorescent RPE cytoplasmic inclusions, and activation of, and dependence upon, the HGF/c-Met pathway.

Conclusions HGF/c-Met pathway confers RPE resistance to loss of mitochondrial function but at the expense of epithelial integrity and function. This finding suggests an alternative of central tenet of AMD that emphasize the role RPE cell death.