APC-Cdh1 Regulates Neuronal Apoptosis Through Modulating Glycolysis and Pentose-Phosphate Pathway After Oxygen-Glucose Deprivation and Reperfusion
- 127 Downloads
Anaphase-promoting complex (APC) with its coactivator Cdh1 is required to maintain the postmitotic state of neurons via degradation of Cyclin B1, which aims to prevent aberrant cell cycle entry that causes neuronal apoptosis. Interestingly, evidence is accumulating that apart from the cell cycle, APC-Cdh1 also involves in neuronal metabolism via modulating the glycolysis promoting enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3). Here, we showed that under oxygen-glucose deprivation and reperfusion (OGD/R), APC-Cdh1 was decreased in primary cortical neurons. Likewise, the neurons exhibited enhanced glycolysis when oxygen supply was reestablished during reperfusion, which was termed as the “neuronal Warburg effect.” In particular, the reperfused neurons showed elevated PFKFB3 expression in addition to a reduction in glucose 6-phosphate dehydrogenase (G6PD). Such changes directed neuronal glucose metabolism from pentose-phosphate pathway (PPP) to aerobic glycolysis compared to the normal neurons, resulting in increased ROS production and apoptosis during reperfusion. Pretreatment of neurons with Cdh1 expressing lentivirus before OGD could reverse this metabolic shift and attenuated ROS-induced apoptosis. However, the metabolism regulation and neuroprotection by Cdh1 under OGD/R condition could be blocked when co-transfecting neurons with Ken box-mut-PFKFB3 (which is APC-Cdh1 insensitive). Based on these data, we suggest that the Warburg effect may contribute to apoptotic mechanisms in neurons under OGD/R insult, and targeting Cdh1 may be a potential therapeutic strategy as both glucose metabolic regulator and apoptosis suppressor of neurons in brain injuries.
KeywordsAerobic glycolysis Cdh1 Neuron Oxygen-glucose deprivation Pentose-phosphate pathway
This work was supported by the National Natural Science Foundation of China (Grant No. 81600965).
YZ and LW designed the study; ZL and BZ performed the experiments; ZL and WY collected the data and performed the analysis; ZL and CZ wrote the initial draft; YZ contributed towards manuscript improvement and revision.
Compliance with Ethical Standards
Conflict of interest
The author(s) declared they have no financial relationship with the organization that sponsored the research and have no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
- Bolaños JP, Almeida A (2010) The Pentose-Phosphate Pathway in Neuronal Survival Against Nitrosative Stress. IUBMB Life 62:14–18Google Scholar
- Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11:37–51CrossRefGoogle Scholar
- Hu R, Li L, Li D, Tan W, Wan L, Zhu C, Zhang Y, Zhang C, Yao W (2016) Downregulation of Cdh1 signaling in spinal dorsal horn contributes to the maintenance of mechanical allodynia after nerve injury in rats. Mol Pain 12:1–16Google Scholar
- Støttrup NB, Løfgren B, Birkler RD, Nielsen JM, Wang L, Caldarone CA, Kristiansen SB, Contractor H, Johannsen M, Bøtker HE, Nielsen TT (2010) Inhibition of the malate–aspartate shuttle by pre-ischaemic aminooxyacetate loading of the heart induces cardioprotection. Cardiovasc Res 88:257–266CrossRefGoogle Scholar
- Vander Heiden MG, Christofk HR, Schuman E, Subtelny AO, Sharfi H, Harlow EE, Xian J, Cantlay LC (2010) Identification of small molecule inhibitors of pyruvate kinase M2. Pharm Biol 79:1118–1124Google Scholar