Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany.
BMC Biol. 2020 Mar 18;18(1):31. doi: 10.1186/s12915-020-0760-3.
Metabolic activity alternates between high and low states during different stages of an organism's life cycle. During the transition from growth to quiescence, a major metabolic shift often occurs from oxidative phosphorylation to glycolysis and gluconeogenesis. We use the entry of Caenorhabditis elegans into the dauer larval stage, a developmentally arrested stage formed in response to harsh environmental conditions, as a model to study the global metabolic changes and underlying molecular mechanisms associated with growth to quiescence transition.
Here, we show that the metabolic switch involves the concerted activity of several regulatory pathways. Whereas the steroid hormone receptor DAF-12 controls dauer morphogenesis, the insulin pathway maintains low energy expenditure through DAF-16/FoxO, which also requires AAK-2/AMPKα. DAF-12 and AAK-2 separately promote a shift in the molar ratios between competing enzymes at two key branch points within the central carbon metabolic pathway diverting carbon atoms from the TCA cycle and directing them to gluconeogenesis. When both AAK-2 and DAF-12 are suppressed, the TCA cycle is active and the developmental arrest is bypassed.
The metabolic status of each developmental stage is defined by stoichiometric ratios within the constellation of metabolic enzymes driving metabolic flux and controls the transition between growth and quiescence.
在生物体生命周期的不同阶段，代谢活动在高和低状态之间交替。在从生长到静止的转变过程中，代谢通常会从氧化磷酸化转变为糖酵解和糖异生。我们使用秀丽隐杆线虫进入 dauer 幼虫期作为模型，研究与从生长到静止的转变相关的全局代谢变化和潜在的分子机制。dauer 幼虫期是一种发育停滞的阶段，是对恶劣环境条件的反应形成的。
在这里，我们表明代谢转换涉及几个调节途径的协同活动。甾体激素受体 DAF-12 控制 dauer 形态发生，而胰岛素途径通过 DAF-16/FoxO 维持低能量消耗，DAF-16/FoxO 也需要 AAK-2/AMPKα。DAF-12 和 AAK-2 分别促进中央碳代谢途径中两个关键分支点处竞争酶的摩尔比发生变化，将碳原子从 TCA 循环中转移并引导它们进行糖异生。当同时抑制 AAK-2 和 DAF-12 时，TCA 循环活跃，发育停滞被绕过。
每个发育阶段的代谢状态由驱动代谢通量的代谢酶的化学计量比定义，并控制生长和静止之间的转变。
