mTOR inhibition attenuates glucose deprivation-induced death in photoreceptors via suppressing a mitochondria-dependent apoptotic pathway.

Acute energy depletion contributes to ischemia-induced retinal neuronal injury, causing photoreceptor death and subsequent vision loss. The mTOR pathway is a crucial cellular signaling hub modulating RNA transcription, protein synthesis, and metabolic balance. Thus, we mimicked acute energy depletion in photoreceptor cells (661W cells) with glucose deprivation and investigated neuroprotective mechanisms of mTOR inhibition. We found that treatment with rapamycin, an mTOR-specific inhibitor, reduced intracellular ROS, maintained the mitochondrial membrane potential and restored mitochondrial dysfunction. In addition, inhibiting the mTOR signal suppressed DRP1 translocation to the mitochondria, pro-apoptotic mitochondrial protein release, and caspase 3 activation when glucose was deprived. Inhibition of mTOR offers significant neuroprotection against glucose deprivation-induced injury in 661W cells, chiefly via suppressing mitochondrial-dependent pathways. These observations may shed light on treating ischemia-related retinal diseases.

Inhibition of mTOR signaling protects photoreceptor cells against serum deprivation by reducing oxidative stress and inducing G2/M cell cycle arrest.

The mammalian target of rapamycin (mTOR) pathway is a crucial cellular signaling hub, which integrates internal and external cues to modulate the cell cycle, protein synthesis and metabolism. The present study hypothesized that inhibiting mTOR signaling may induce cells to enter lower and more stable bioenergetic states, in which neurons have greater resistance to various insults. Neurotrophin withdrawal from photoreceptor cells (661W cells) was mimicked using serum deprivation, and the neuroprotective mechanisms were studied following suppression of the mTOR pathway. Treatment with an mTOR specific inhibitor, rapamycin, reduced intracellular levels of reactive oxygen species, suppressed oxidative stress, and attenuated mitochondrial dysfunction. In addition, inhibiting mTOR signaling induced a G2/M cell cycle arrest, thus providing an opportunity to repair damaged DNA and block the cell death cascade. These results suggested that inhibition of mTOR had a neuroprotective effect on serum­deprived 661W cells. In conclusion, the mTOR pathway is a critical molecular signal for cell cycle regulation and energy metabolism, and inhibiting the mTOR pathway may attenuate neurotrophin withdrawal­induced damage. These observations may provide evidence for the treatment of retinal degenerative disease, since inducing neurons into a lower and more stable bioenergetic state by blocking mTOR signaling may slow the progression of neurodegenerative diseases.