Altered Energy Metabolism During Early Optic Nerve Crush Injury: Implications of Warburg-Like Aerobic Glycolysis in Facilitating Retinal Ganglion Cell Survival

Abstract

Neurons, especially axons, are metabolically demanding and energetically vulnerable during injury. However, the exact energy budget alterations that occur early after axon injury and the effects of these changes on neuronal survival remain unknown. Using a classic mouse model of optic nerve-crush injury, we found that traumatized optic nerves and retinas harbor the potential to mobilize two primary energetic machineries, glycolysis and oxidative phosphorylation, to satisfy the robustly increased adenosine triphosphate (ATP) demand. Further exploration of metabolic activation showed that mitochondrial oxidative phosphorylation was amplified over other pathways, which may lead to decreased retinal ganglion cell (RGC) survival despite its supplement to ATP production. Gene set enrichment analysis of a microarray (GSE32309) identified significant activation of oxidative phosphorylation in injured retinas from wild-type mice compared to those from mice with deletion of phosphatase and tensin homolog (PTEN), while PTEN-/-mice had more robust RGC survival. Therefore, we speculated that the oxidation-favoring metabolic pattern after optic nervecrush injury could be adverse for RGC survival. After redirecting metabolic flux toward glycolysis (magnifying the Warburg effect) using the drug meclizine, we successfully increased RGC survival. Thus, we provide novel insights into a potential bioenergetics-based strategy for neuroprotection.

Opposing Effects of ApoE2 and ApoE4 on Glycolytic Metabolism in Neuronal Aging Supports a Warburg Neuroprotective Cascade against Alzheimer’s Disease

“…The present study highlights the potentially crucial role of HK-driven glycolytic phenotypes in conferring neuronal resilience or vulnerability associated with ApoE genetic variants to AD. Our findings lend compelling support to the recently proposed inverse-Warburg origin of AD and present a novel and exciting opportunity in the prevention and treatment of AD [16,66,67,89].…”

Investigation on the expression regulation of RIPK1/RIPK3 in the retinal ganglion cells (RGCs) cultured in high glucose

“…The bottom of the centrifuge tube was flicked gently to disperse the cells avoiding clumps. A 5 μL of Thy1.2 antibody was added to a flow cytometry tube and a 50 μL Staining Buffer to an empty tube [ 19 ]. To each tube, 50 μL cell suspension was added (approximately 10 6 cells), mixed gently, and incubated at 4°C for 20 min.…”

Therapeutic role of PTEN in tissue regeneration for management of neurological disorders: stem cell behaviors to an in-depth review

“…This suggests that trans-differentiation of human adult stem cells is the basis for the advancement of personalized medicine [ 58 ]. Furthermore, genetic deletion of PTEN and PTEN peptide promotes axonal regeneration in damaged optic nerves, improving functional recovery after nervous system injury [ 59 , 60 ]. While PTEN is a known tumor suppressor, research has found that prolonged loss of PTEN in adult neurons can improve neuronal health [ 61 ].…”