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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Updates to a 13 C metabolic flux analysis model for evaluating energy metabolism in cultured cerebellar granule neurons from neonatal rats
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Updates to a 13 C metabolic flux analysis model for evaluating energy metabolism in cultured cerebellar granule neurons from neonatal rats

机译：关于评估新生大鼠培养的小脑颗粒神经元的能量代谢的13 C代谢通量分析模型的更新

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Abstract A hexose phosphate recycling model previously developed to infer fluxes through the major glucose consuming pathways in cultured cerebellar granule neurons (CGNs) from neonatal rats metabolizing [1,2– 13 C 2 ]glucose was revised by considering reverse flux through the non-oxidative pentose phosphate pathway (PPP) and symmetrical succinate oxidation within the tricarboxylic acid (TCA) cycle. The model adjusts three flux ratios to effect 13 C distribution in the hexose, pentose, and triose phosphate pools, and in TCA cycle malate to minimize the error between predicted and measured 13 C labeling in exported lactate (i.e., unlabeled, single-, double-, and triple-labeled; M, M1, M2, and M3, respectively). Inclusion of reverse non-oxidative PPP flux substantially increased the number of calculations but ultimately had relatively minor effects on the labeling of glycolytic metabolites. From the error-minimized solution in which the predicted M-M3 lactate differed by 0.49% from that measured by liquid chromatography-triple quadrupole mass spectrometry, the neurons exhibited negligible forward non-oxidative PPP flux. Thus, no glucose was used by the pentose cycle despite explicit consideration of hexose phosphate recycling. Mitochondria consumed only 16% of glucose while 45% was exported as lactate by aerobic glycolysis. The remaining 39% of glucose was shunted to pentose phosphates presumably for de novo nucleotide synthesis, but the proportion metabolized through the oxidative PPP vs. the reverse non-oxidative PPP could not be determined. The lactate exported as M1 (2.5%) and M3 (1.2%) was attributed to malic enzyme, which was responsible for 7.8% of pyruvate production (vs. 92.2% by glycolysis). The updated model is more broadly applicable to different cell types by considering bi-directional flux through the non-oxidative PPP. Its application to cultured neurons utilizing glucose as the sole exogenous substrate has demonstrated substantial oxygen-independent glucose utilization by aerobic glycolysis as well as the oxidative PPP and/or reverse non-oxidative PPP, but negligible glucose consumption by the pentose cycle. Highlights ? Reverse non-oxidative PPP flux was incorporated in a 13 C metabolic flux model. ? The model was applied to cerebellar granule neurons from neonatal rat brains. ? The oxidative and reverse non-oxidative PPP consumed 39% of the glucose. ? Glucose consumption by the pentose cycle was negligible. ? The updated model offers advantages to assessing pathway fluxes.
机译：摘要通过考虑通过非氧化的反向通量来修订前通过培养的小脑颗粒神经元（CGNS）中的主要葡萄糖颗粒神经元（CGNS）中的主要葡萄糖消耗途径（CGNS）来推断出来的磷酸磷酸盐回收模型。通过考虑通过非氧化逆转戊糖磷酸盐途径（PPP）和三羧酸（TCA）循环内的对称琥珀酸氧化。该模型调整三种助焊剂比率，以实现己糖，戊糖和三糖磷酸盐池中的13℃分布，并且在TCA循环中，苹果醇最小化预测和测量的导出乳酸中的误差（即，未标记，单，双 - 和三重标记; m，m1，m2和m3）。包含反向非氧化PPP通量基本上增加了计算的数量，但最终对糖酵解代谢物的标记产生了相对较小的影响。从误差最小化的解决方案，其中预测的M-M3乳酸盐从液相色谱 - 三倍四极杆质谱法测量的0.49％，神经元表现出可忽略的前后非氧化PPP通量。因此，尽管戊糖磷酸盐再循环明确考虑，但戊酮循环不使用葡萄糖。线粒体仅消耗16％的葡萄糖，而45％以有氧糖醇分析出口乳酸。剩余的39％的葡萄糖被分流以戊糖磷酸盐，但是对于De Novo核苷酸合成，而是通过氧化PPP与氧化PPP与逆向非氧化PPP代谢的比例。出口为M1（2.5％）和M3（1.2％）的乳酸归因于苹型育酵母，其负责7.8％的丙酮酸生产（通过糖酵解5.2.2％）。通过考虑通过非氧化PPP的双向通量，更新的模型更广泛适用于不同的细胞类型。其在利用葡萄糖作为唯一外源基质的培养神经元的应用已经证明了通过有氧糖醇分解的大量氧无血糖利用以及氧化PPP和/或反向非氧化PPP，但戊糖循环可忽略不计的葡萄糖消耗。强调 ？逆转非氧化PPP通量掺入13℃代谢助熔剂模型中。还该模型应用于来自新生大鼠大脑的小脑颗粒神经元。还氧化和反向非氧化PPP消耗了39％的葡萄糖。还戊糖循环的葡萄糖消耗可忽略不计。还更新的型号提供了评估途径通量的优势。

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