Calcium signals tune AMPK activity and mitochondrial homeostasis in dendrites of developing neurons

The growth of dendritic arbors in developing neurons is known to be regulated by neuronal activity, which is thought as one of the mechanisms of neural circuit optimization. Here we demonstrate that activity-dependent calcium signaling controls mitochondrial homeostasis and dendritic outgrowth via AMP-activated protein kinase (AMPK) in developing hippocampal neurons. AMPK deficiency phenocopies the inhibition of neuronal activity, inducing dendritic hypotrophy with abnormally elongated mitochondria. In growing dendrites, AMPK is activated by neuronal activity and dynamically oscillates in synchrony with calcium spikes, and this AMPK oscillation is inhibited by CaMKK2 knockdown. AMPK activation leads to phosphorylation of MFF and ULK1, which initiate mitochondrial fission and mitophagy, respectively. Dendritic mitochondria in AMPK-depleted neurons exhibit impaired fission and mitophagy and display multiple signs of dysfunction. Thus, AMPK activity is finely tuned by the calcium-CaMKK2 pathway and regulates mitochondrial homeostasis by facilitating removal of damaged components in rapidly growing neurons during normal brain development.