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Casey J Keuthan, Cassidy M Chason, John D Ash; A non-redundant role for PGC-1β in retinal homeostasis and photoreceptor resistance to oxidative stress induced by light exposure. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3016. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) family members are considered master regulators of mitochondrial biogenesis and metabolism. Although PGC-1 has been studied in a variety of high-energy tissues, the non-redundancies between the individual PGC-1α and PGC-1β isoforms are not well established. Moreover, the function of PGC-1β in the retina remains largely unknown. This work aimed to further elucidate the role of PGC-1β in photoreceptor protection during aging and in light stress conditions.
Chx10Cre;PGC-1βf/f mice are conditional knockouts (cKO) of PGC-1β in retinal neurons and Müller glial cells. Littermates not expressing Cre were used as controls. All animals were reared in dim light conditions (<100 lux). For light stress, mice were exposed to light (400 lux or greater). Spectral Domain Optical Coherence Tomography (SD-OCT) was used to study retinal morphology, and retinal function was measured by electroretinography (ERG). Retinas were collected for quantitative RT-PCR (qRT-PCR) to measure mRNA expression. All procedures with animals were conducted in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.
In dim light, young adult (2 months) PGC-1β cKO mice had normal retinas, suggesting these mice had normal retinal development. As cKO mice aged, ONL thinning was observed around 6-9 months by OCT. Around 15 months of age, there was a decrease in cardiolipin synthase and acetyl-CoA carboxylase expression, but no significant changes were observed in oxidative stress markers or mitochondrial-related genes involved in oxidative phosphorylation. Interestingly, young cKO mice were more sensitive to light stress, since they were damaged by light levels that are normally non-damaging in wild-type mice. This included significant outer nuclear layer (ONL) thinning and reduced ERG a-wave amplitudes. Differences in PGC-1α mRNA expression were not obvious in light stressed or aged mice.
Our data suggest a critical role for PGC-1β in photoreceptor survival with age and protection from light stress. This role could not be compensated by PGC-1α. We hypothesize that PGC-1β plays a non-redundant role in mitigating metabolic stress of aging and light-induced oxidative damage. This role may involve maintenance of lipid synthesis and other mitochondrial-related processes.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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