The AMPK-dependent inhibition of autophagy plays a crucial role in protecting photoreceptor from photooxidative injury

Abstract

Excessive light exposure can potentially cause irreversible damage to the various photoreceptor cells, and this aspect has been considered as an important factor leading to the progression of the different retinal diseases. AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR) are crucial intracellular signaling hubs involved in the regulation of cellular metabolism, energy homeostasis, cellular growth and autophagy. A number of previous studies have indicated that either AMPK activation or mTOR inhibition can promote autophagy in most cases. In the current study, we have established an in vitro as well as in vivo photooxidation-damaged photoreceptor model and investigated the possible influence of visible light exposure in the AMPK/mTOR/autophagy signaling pathway. We have also explored the potential regulatory effects of AMPK/mTOR on light-induced autophagy and protection achieved by suppressing autophagy in photooxidation-damaged photoreceptors. We observed that light exposure led to a significant activation of mTOR and autophagy in the photoreceptor cells. However, intriguingly, AMPK activation or mTOR inhibition significantly inhibited rather than promoting autophagy, which was termed as AMPK-dependent inhibition of autophagy. In addition, either indirectly suppressing autophagy by AMPK activation/ mTOR inhibition or directly blocking autophagy with an inhibitor exerted a significant protective effect on the photoreceptor cells against the photooxidative damage. Neuroprotective effects caused by the AMPK-dependent inhibition of autophagy were also verified with a retinal light injured mouse model in vivo. Overall, our findings demonstrated that AMPK / mTOR pathway could inhibit autophagy through AMPK-dependent inhibition of autophagy to significantly protect the photoreceptors from photooxidative injury, which may aid to further develop novel targeted retinal neuroprotective drugs.

Keywords: AMPK; Autophagy; Photooxidation; Photoreceptor; Retinal light injury; Retinal neuroprotection.