Abstract
The retinal pigment epithelium (RPE) supports visual processing and photoreceptor homeostasis via energetically demanding cellular functions. Here, we describe the consequences of repressing peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α), a master regulator of mitochondrial function and biogenesis, on RPE epithelial integrity. The sustained silencing of PGC-1α in differentiating human RPE cells affected mitochondria/autophagy function, redox state, and impaired energy sensor activity ultimately inducing epithelial to mesenchymal transition (EMT). Adult conditional knockout of PGC-1 coactivators in mice resulted in rapid RPE dysfunction and transdifferentiation associated with severe photoreceptor degeneration. RPE anomalies were characteristic of autophagic defect and mesenchymal transition comparable with the ones observed in age-related macular degeneration. These findings demonstrate that PGC-1α is required to maintain the functional and phenotypic status of RPE by supporting the cells' oxidative metabolism and autophagy-mediated repression of EMT.
Highlights
The retina pigment epithelium (RPE) is a highly specialized monolayer of pigmented cuboidal cells separating the neural retina from the choroidal vasculature and serving critical roles to maintain retinal homeostasis and visual function
Because PGC-1α is a major regulator of mitochondrial function, it may be an important player in age-related macular degeneration (AMD) pathogenesis (Kaarniranta et al, 2018) and global knockout mouse models for PGC-1α have been found to mimic some of the degenerative processes characteristic of human AMD (Egger et al, 2012; Zhang et al, 2018)
Evaluation of mitochondrial OXPHOS by extracellular flux analysis and measurement of the oxygen consumption rate (OCR) revealed that loss of PGC-1⍺ decreased all phases of respiration as early as day 7 (Fig 1F)
Summary
The retina pigment epithelium (RPE) is a highly specialized monolayer of pigmented cuboidal cells separating the neural retina from the choroidal vasculature and serving critical roles to maintain retinal homeostasis and visual function. In vitro maturation of human RPE cells was found to be correlated with increased mitochondrial biogenesis and oxidative metabolism (Adijanto & Philp, 2014; Iacovelli et al, 2016). Decreased expression or signaling of key components of the RPE antioxidant mechanism and increase in mitochondrial DNA damage from oxidative stress have been described in aged and AMD eyes (Lin et al, 2011; Golestaneh et al, 2016). Mitochondrial defects and increased sensitivity of oxidative damage associated with PGC1α repression were observed in iPS-derived RPE cells from dry AMD patients (Golestaneh et al, 2016), suggesting that RPE metabolic alteration and oxidative damage act as key initiating events in the activation of the various degenerative mechanisms associated with AMD pathogenesis. A direct implication for PGC-1α in AMD pathogenesis remains to be determined, it is clear that its expression and function are tightly correlated with RPE viability and function
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