The cross-talk of energy sensing and mitochondrial anchoring sustains synaptic efficacy by maintaining presynaptic metabolism.

Sunan Li, Gui-Jing Xiong, Ning Huang, Zu-Hang Sheng

Nature metabolism 2020 Oct

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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.

Citation

Sunan Li, Gui-Jing Xiong, Ning Huang, Zu-Hang Sheng. The cross-talk of energy sensing and mitochondrial anchoring sustains synaptic efficacy by maintaining presynaptic metabolism. Nature metabolism. 2020 Oct;2(10):1077-1095