Mitochondria supply ATP essential for synaptic transmission. Neurons face exceptional challenges in maintaining energy homoeostasis at synapses. Regulation of mitochondrial trafficking and anchoring is critical for neurons to meet increased energy consumption during sustained synaptic activity. However, mechanisms recruiting and retaining presynaptic mitochondria in sensing synaptic ATP levels remain elusive. Here we reveal an energy signalling axis that controls presynaptic mitochondrial maintenance. Activity-induced presynaptic energy deficits can be rescued by recruiting mitochondria through the AMP-activated protein kinase (AMPK)–p21-activated kinase (PAK) energy signalling pathway. Synaptic activity induces AMPK activation within axonal compartments and AMPK–PAK signalling triggers phosphorylation of myosin VI, which drives mitochondrial recruitment and syntaphilin-mediated anchoring on presynaptic filamentous actin. This pathway maintains presynaptic energy supply and calcium clearance during intensive synaptic activity. Disrupting this signalling cross-talk triggers local energy deficits and intracellular calcium build-up, leading to impaired synaptic efficacy during trains of stimulation and reduced recovery from synaptic depression after prolonged synaptic activity. Our study reveals a mechanistic cross-talk between energy sensing and mitochondria anchoring to maintain presynaptic metabolism, thus fine-tuning short-term synaptic plasticity and prolonged synaptic efficacy.

线粒体提供突触传递所必需的 ATP。神经元在维持突触能量稳态方面面临着特殊的挑战。线粒体运输和锚定的调节对于神经元在持续突触活动期间满足增加的能量消耗至关重要。然而，在感知突触 ATP 水平时招募和保留突触前线粒体的机制仍然难以捉摸。在这里，我们揭示了控制突触前线粒体维持的能量信号轴。活动引起的突触前能量缺陷可以通过 AMP 激活蛋白激酶 (AMPK)–p21 激活激酶 (PAK) 能量信号通路招募线粒体来缓解。突触活动诱导轴突室内的 AMPK 激活，AMPK-PAK 信号传导触发肌球蛋白 VI 的磷酸化，从而驱动线粒体募集和亲亲亲和蛋白介导的突触前丝状肌动蛋白锚定。该途径在密集的突触活动期间维持突触前能量供应和钙清除。破坏这种信号串扰会引发局部能量不足和细胞内钙积聚，导致一系列刺激期间突触功效受损，并在长时间突触活动后从突触抑制中恢复减少。我们的研究揭示了能量传感和线粒体锚定之间的机制串扰，以维持突触前代谢，从而微调短期突触可塑性和延长突触功效。