We analyzed early brain metabolic adaptations in response to mitochondrial dysfunction in a mouse model of mitochondrial encephalopathy with complex IV deficiency [neuron-specific COX10 knockout (KO)]. In this mouse model, the onset of the mitochondrial defect did not coincide with immediate cell death, suggesting early adaptive metabolic responses to compensate for the energetic deficit. Metabolomic analysis in the KO mice revealed increased levels of glycolytic and pentose phosphate pathway intermediates, amino acids and lysolipids. Glycolysis was modulated by enhanced activity of glycolytic enzymes, and not by their overexpression, suggesting the importance of post-translational modifications in the adaptive response. Glycogen synthase kinase 3 inactivation was the most upstream regulation identified, implying that it is a key event in this adaptive mechanism. Because neurons are thought not to rely on glycolysis for adenosine triphosphate production in normal conditions, our results indicate that neurons still maintain their ability to upregulate this pathway when under mitochondrial respiration stress.

中文翻译：

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增强的糖酵解和 GSK3 失活促进神经元线粒体应激后的大脑代谢适应

我们分析了复杂 IV 缺乏的线粒体脑病小鼠模型中线粒体功能障碍的早期脑代谢适应 [神经元特异性 COX10 敲除 (KO)]。在这个小鼠模型中，线粒体缺陷的发生与细胞立即死亡并不同时发生，这表明早期的适应性代谢反应可以弥补能量不足。KO 小鼠的代谢组学分析显示糖酵解和戊糖磷酸途径中间体、氨基酸和溶血脂的水平增加。糖酵解是通过增强的糖酵解酶活性来调节的，而不是通过它们的过表达来调节，这表明翻译后修饰在适应性反应中的重要性。糖原合酶激酶 3 失活是确定的最上游调节，暗示它是这种自适应机制中的关键事件。因为在正常条件下，神经元被认为不依赖糖酵解来产生三磷酸腺苷，所以我们的结果表明，在线粒体呼吸压力下，神经元仍然保持上调该途径的能力。