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.

中文翻译：

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RPE中PGC-1α的丢失会诱导间质转化并促进视网膜变性。

视网膜色素上皮（RPE）通过功能强大的细胞功能支持视觉处理和感光体稳态。在这里，我们描述了抑制过氧化物酶体增殖物激活的受体γcoactivator-1α（PGC-1α），线粒体功能和生物发生的主要调节者对RPE上皮完整性的影响。PGC-1α在分化的人类RPE细胞中的持续沉默影响线粒体/自噬功能，氧化还原状态和能量传感器活性受损，最终诱导上皮向间质转化（EMT）。成年小鼠中PGC-1共激活剂的条件性基因敲除导致快速RPE功能障碍和转分化，与严重的感光细胞变性有关。RPE异常具有自噬缺陷和间充质转变的特征，与年龄相关性黄斑变性所观察到的异常相当。这些发现表明，PGC-1α通过支持细胞的氧化代谢和自噬介导的EMT抑制来维持RPE的功能和表型状态。