PGC-1α Determines Light Damage Susceptibility of the Murine Retina

The peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) proteins are key regulators of cellular bioenergetics and are accordingly expressed in tissues with a high energetic demand. For example, PGC-1 alpha and PGC-1 beta control organ function of brown adipose tissue, heart, brain, liver and skeletal muscle. Surprisingly, despite their prominent role in the control of mitochondrial biogenesis and oxidative metabolism, expression and function of the PGC-1 coactivators in the retina, an organ with one of the highest energy demands per tissue weight, are completely unknown. Moreover, the molecular mechanisms that coordinate energy production with repair processes in the damaged retina remain enigmatic. In the present study, we thus investigated the expression and function of the PGC-1 coactivators in the healthy and the damaged retina. We show that PGC-1 alpha and PGC-1 beta are found at high levels in different structures of the mouse retina, most prominently in the photoreceptors. Furthermore, PGC-1 alpha knockout mice suffer from a striking deterioration in retinal morphology and function upon detrimental light exposure. Gene expression studies revealed dysregulation of all major pathways involved in retinal damage and apoptosis, repair and renewal in the PGC-1 alpha knockouts. The light-induced increase in apoptosis in vivo in the absence of PGC-1 alpha was substantiated in vitro, where overexpression of PGC-1 alpha evoked strong anti-apoptotic effects. Finally, we found that retinal levels of PGC-1 expression are reduced in different mouse models for retinitis pigmentosa. We demonstrate that PGC-1 alpha is a central coordinator of energy production and, importantly, all of the major processes involved in retinal damage and subsequent repair. Together with the observed dysregulation of PGC-1 alpha and PGC-1 beta in retinitis pigmentosa mouse models, these findings thus imply that PGC-1 alpha might be an attractive target for therapeutic approaches aimed at retinal degeneration diseases.