The shift of carbon utilization from primarily glucose to other nutrients is a fundamental metabolic adaptation to cope with decreased blood glucose levels and the consequent decline in glucose oxidation. AMP-activated protein kinase (AMPK) plays crucial roles in this metabolic adaptation. However, the underlying mechanism is not fully understood. Here, we show that PDZ domain containing 8 (PDZD8), which we identify as a new substrate of AMPK activated in low glucose, is required for the low glucose-promoted glutaminolysis. AMPK phosphorylates PDZD8 at threonine 527 (T527) and promotes the interaction of PDZD8 with and activation of glutaminase 1 (GLS1), a rate-limiting enzyme of glutaminolysis. In vivo, the AMPK-PDZD8-GLS1 axis is required for the enhancement of glutaminolysis as tested in the skeletal muscle tissues, which occurs earlier than the increase in fatty acid utilization during fasting. The enhanced glutaminolysis is also observed in macrophages in low glucose or under acute lipopolysaccharide (LPS) treatment. Consistent with a requirement of heightened glutaminolysis, the PDZD8-T527A mutation dampens the secretion of pro-inflammatory cytokines in macrophages in mice treated with LPS. Together, we have revealed an AMPK-PDZD8-GLS1 axis that promotes glutaminolysis ahead of increased fatty acid utilization under glucose shortage.

碳利用从主要葡萄糖转向其他营养素是一种基本的代谢适应，以应对血糖水平下降和随之而来的葡萄糖氧化下降。 AMP 激活蛋白激酶 (AMPK) 在这种代谢适应中发挥着至关重要的作用。然而，其根本机制尚不完全清楚。在这里，我们发现含有 PDZ 结构域 8 (PDZD8) 的 PDZ 结构域是低糖促进的谷氨酰胺分解所必需的，我们将其确定为低糖条件下激活的 AMPK 的新底物。 AMPK 在苏氨酸 527 (T527) 处磷酸化 PDZD8，并促进 PDZD8 与谷氨酰胺酶 1 (GLS1)（一种谷氨酰胺分解限速酶）的相互作用并激活谷氨酰胺酶 1 (GLS1)。在体内，AMPK-PDZD8-GLS1 轴对于增强谷氨酰胺分解是必需的，正如在骨骼肌组织中所测试的那样，谷氨酰胺分解的发生早于禁食期间脂肪酸利用率的增加。在低葡萄糖或急性脂多糖（LPS）处理下的巨噬细胞中也观察到谷氨酰胺分解增强。与增强谷氨酰胺分解的要求一致，PDZD8-T527A 突变抑制了用 LPS 治疗的小鼠巨噬细胞中促炎细胞因子的分泌。我们共同揭示了一个 AMPK-PDZD8-GLS1 轴，在葡萄糖短缺的情况下，该轴在增加脂肪酸利用率之前促进谷氨酰胺分解。