The energy cost of neuronal activity is mainly sustained by glucose^1,2. However, in an apparent paradox, neurons modestly metabolize glucose through glycolysis^3,4,5,6, a circumstance that can be accounted for by the constant degradation of 6-phosphofructo-2-kinase–fructose-2,6-bisphosphatase-3 (PFKFB3)^3,7,8, a key glycolysis-promoting enzyme. To evaluate the in vivo physiological importance of this hypoglycolytic metabolism, here we genetically engineered mice with their neurons transformed into active glycolytic cells through Pfkfb3 expression. In vivo molecular, biochemical and metabolic flux analyses of these neurons revealed an accumulation of anomalous mitochondria, complex I disassembly, bioenergetic deficiency and mitochondrial redox stress. Notably, glycolysis-mediated nicotinamide adenine dinucleotide (NAD⁺) reduction impaired sirtuin-dependent autophagy. Furthermore, these mice displayed cognitive decline and a metabolic syndrome that was mimicked by confining Pfkfb3 expression to hypothalamic neurons. Neuron-specific genetic ablation of mitochondrial redox stress or brain NAD⁺ restoration corrected these behavioural alterations. Thus, the weak glycolytic nature of neurons is required to sustain higher-order organismal functions.

神经元活动的能量消耗主要由葡萄糖维持^1,2 。然而，在一个明显的悖论中，神经元通过糖酵解适度代谢葡萄糖^3,4,5,6 ，这种情况可以通过 6-磷酸果糖-2-激酶 - 果糖-2,6-双磷酸酶-3 的不断降解来解释(PFKFB3) ^3,7,8 ，一种关键的糖酵解促进酶。为了评估这种低糖酵解代谢的体内生理重要性，我们对小鼠进行了基因工程改造，通过表达Pfkfb3将其神经元转化为活跃的糖酵解细胞。对这些神经元的体内分子、生化和代谢通量分析揭示了异常线粒体的积累、复合物 I 分解、生物能缺乏和线粒体氧化还原应激。值得注意的是，糖酵解介导的烟酰胺腺嘌呤二核苷酸（NAD ⁺ ）减少会损害sirtuin依赖性自噬。此外，这些小鼠表现出认知能力下降和代谢综合征，这是通过将Pfkfb3表达限制在下丘脑神经元来模拟的。线粒体氧化还原应激的神经元特异性基因消融或大脑 NAD ⁺恢复纠正了这些行为改变。因此，神经元的弱糖酵解性质是维持高阶有机体功能所必需的。