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

Abstract

Dendritic outgrowth in immature neurons is enhanced by neuronal activity and is considered one of the mechanisms of neural circuit optimization. It is known that calcium signals affect transcriptional regulation and cytoskeletal remodeling necessary for dendritic outgrowth. Here we demonstrate that activity-dependent calcium signaling also controls mitochondrial homeostasis via AMP-activated protein kinase (AMPK) in growing dendrites of differentiating hippocampal neurons. We found that the inhibition of neuronal activity induces 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. Genetic inhibition of fission leads to dendritic hypoplasia reminiscent of AMPK deficient neurons. Thus, AMPK activity is finely tuned by the calcium-CaMKK2 pathway and regulates mitochondrial homeostasis by facilitating removal of damaged components of mitochondria in growing neurons during normal brain development.