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

Abstract

The peroxisome proliferator-activated receptor γ 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-1α and PGC-1β 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-1α and PGC-1β are found at high levels in different structures of the mouse retina, most prominently in the photoreceptors. Furthermore, PGC-1α 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-1α knockouts. The light-induced increase in apoptosis in vivo in the absence of PGC-1α was substantiated in vitro, where overexpression of PGC-1α 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-1α 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-1α and PGC-1β in retinitis pigmentosa mouse models, these findings thus imply that PGC-1α might be an attractive target for therapeutic approaches aimed at retinal degeneration diseases.

Repressed SIRT1/PGC-1α pathway and mitochondrial disintegration in iPSC-derived RPE disease model of age-related macular degeneration

“…Its repression is associated with obesity, diabetes, neurodegeneration, and cardiomyopathy disorders [23–27]. A role for PGC-1α in determining light damage susceptibility and regulating normal and pathological angiogenesis in the retina has also been reported [24, 67]. A recent study proposed a role for PGC-1α in induction of human RPE oxidative metabolism and antioxidant capacity [29].…”

New insights into PGC‐1 coactivators: redefining their role in the regulation of mitochondrial function and beyond

“…A recent study by Egger et al . has found that mice lacking PGC‐1α exhibit normal retinal function and morphology under basal, unstressed conditions, when mice are adapted to darkness. However, consistent with the role of PGC‐1α in the adaptation to diverse stress stimuli or environmental situations, a lack of this coactivator renders PGC‐1α knockout mice more susceptible to light damage.…”

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

“…PGC-1 also plays a role in light damage-induced retinal regeneration and function and in chondrogenesis [134,135]. PGC-1 is further implicated in osteoclast activation and PRC has a nonredundant function in proliferative growth [136,137].…”