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

AMP-activated protein kinase (AMPK) governs multiple pathways regulating mitochondrial dynamics and homeostasis. AMPK overactivation is a hallmark of some neurodegenerative diseases, leading to excessive mitochondrial fission and mitophagy and subsequent degeneration of neuronal processes. Here we demonstrate that AMPK is involved in activity-dependent dendritic outgrowth of 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.