mTORC2 activation protects retinal ganglion cells via Akt signaling after autophagy induction in traumatic optic nerve injury

Abstract

Traumatic optic neuropathy is an injury to the optic nerve that leads to vision loss. Autophagy is vital for cell survival and cell death in central nervous system injury, but the role of autophagy in traumatic optic nerve injury remains uncertain. Optic nerve crush is a robust model of traumatic optic nerve injury. p62 siRNA and rapamycin are autophagy inducers and have different neuroprotective effects in the central nervous system. In this study, p62 and rapamycin induced autophagy, but only p62 siRNA treatment provided a favorable protective effect in visual function and retinal ganglion cell (RGC) survival. Moreover, the number of macrophages at the optic nerve lesion site was lower in the p62-siRNA-treated group than in the other groups. p62 siRNA induced more M2 macrophage polarization than rapamycin did. Rapamycin inhibited both mTORC1 and mTORC2 activation, whereas p62 siRNA inhibited only mTORC1 activation and maintained mTORC2 and Akt activation. Inhibition of mTORC2-induced Akt activation resulted in blood–optic nerve barrier disruption. Combined treatment with rapamycin and the mTORC2 activator SC79 improved RGC survival. Overall, our findings suggest that mTORC2 activation after autophagy induction is necessary for the neuroprotection of RGCs in traumatic optic nerve injury and may lead to new clinical applications.

Metabolic Syndrome Triggered by Fructose Diet Impairs Neuronal Function and Vascular Integrity in ApoE-KO Mouse Retinas: Implications of Autophagy Deficient Activation

“…In this in vivo model of MetS, we characterized the effects of metabolic derangement on retinal function over time and analyzed the vascular, neuronal and glial alterations. Finally, given that autophagy deregulation is implicated in many retinal pathologies related to hyperglycemia and dyslipidemia ( Meng et al, 2017 ), we investigated if this cellular homeostatic mechanism ( Kim et al, 2008 ; Rodriguez-Muela et al, 2012 ; Wen et al, 2019 ) was activated in FD-fed ApoE-KO mice, once retinal abnormalities were detected.…”

Protective Efficacy of a Dietary Supplement Based on Forskolin, Homotaurine, Spearmint Extract, and Group B Vitamins in a Mouse Model of Optic Nerve Injury

“…Although it is less clear why IOP elevation selectively compromises RGC survival, a major priority is to protect retinal neurons from death, which necessitates the elucidation of molecular/cellular mechanisms underlying RGC loss. In the ONC model, for instance, blocking the signaling pathway of the cytokine tumor necrosis factor α or activating autophagic processes by selective drugs have been demonstrated effective strategies in improving RGC survival [17,18]. In patients, glaucoma is treated by ocular hypotensive pharmacological approaches that reduce the production of eye fluid and/or improve how fluid drains from the eye [19].…”

Autophagy in the Regulation of Tissue Differentiation and Homeostasis

“…However, in 2017 Esteban-Martinez and collaborators by using a different mouse model (i.e., peritoneal elicited macrophages in CD1 mice) stated that mitophagy contributes to macrophage polarization toward the proinflammatory and more glycolytic M1 phenotype by eliminating mitochondria, but not to M2 macrophage polarization that relies mainly on oxidative phosphorylation (Esteban-Martinez et al, 2017). On the other hand, it seems clear that induction of autophagy supports M2 polarization involving AKT/PI3K pathway, STAT6 and Atg7 (Kapoor et al, 2015; Raben et al, 2008;Masiero et al, 2009;Castets et al, 2013;Nemazanyy et al, 2013;Skobo et al, 2014;Bujak et al, 2015;Fuqua et al, 2019 Muscle Vergadi et al, 2017;Sanjurjo et al, 2018;Wen et al, 2019;Bo et al, 2020).…”