The crosstalk of energy sensing and mitochondrial anchoring sustains synaptic efficacy by maintaining presynaptic metabolism

Mitochondria supply ATP essential for synaptic transmission. Neurons face exceptional challenges in maintaining energy homeostasis 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 signaling axis that controls presynaptic mitochondrial maintenance. Activity-induced presynaptic energy deficits could be rescued by recruiting mitochondria through AMPK-PAK energy signaling pathway. Synaptic activity induces AMPK activation within axonal compartments and AMPK-PAK signaling triggers phosphorylation of myosin-VI, which drives mitochondrial recruitment and syntaphilin-mediated anchoring on presynaptic F-actin. This pathway maintains presynaptic energy supply and calcium clearance during intensive synaptic activity. Disrupting this signaling crosstalk triggers local energy deficits and [Ca(2+)](i) buildup, leading to impaired synaptic efficacy during trains of stimulation, and reduced recovery from synaptic depression after prolonged synaptic activity. Our study reveals a mechanistic crosstalk between energy sensing and mitochondria anchoring to maintain presynaptic metabolism, thus fine-tuning short-term synaptic plasticity and prolonged synaptic efficacy.