A Na+–PINK1 signaling axis couples mitochondrial fission to structural remodeling during synaptic depression
Benjamin Chun-Kit Tong, Inmaculada Segura, Simone Wanderoy, Markus Rehm, Angelika Bettina Harbauer
Abstract
Mitochondrial density in dendrites adapts to the number of synaptic inputs to adequately sustain local ATP and Ca2+ buffering for neuronal signaling. During long-term depression (LTD), synapse elimination is accompanied by activation of caspase-3 through sublethal mitochondria-derived apoptotic signals, driving neurotransmitter receptor internalization and spine shrinking. However, the upstream signals that link synaptic activity to mitochondrial remodeling remain unknown. Here we show that Na+ influx through NMDA receptors depolarizes mitochondria during chemically induced LTD. This triggers stabilization and activation of the PINK1 kinase in a translation-dependent manner, leading to asynchronous mitochondrial fission. Na+ influx and PINK1 are required for cLTD-induced fission, and blocking either Na+ influx or PINK1 prevents caspase-3 activation and spine shrinking in cultured neurons. Together, these findings identify a Na+-PINK1 signaling axis that couples NMDA receptor activity to mitochondrial fission and caspase-3-dependent synapse elimination during LTD, with implications for the homeostatic regulation of synaptic density.
Lay Summary
Long-term depression (LTD) is how the brain weakens and removes some synaptic connections to fine-tune its circuits. This study shows that sodium (Na+) entering the neuron through NMDA receptors activates a protein called PINK1, which makes mitochondria split apart and triggers the enzyme caspase-3 to drive synapse shrinking and removal. Blocking either the sodium influx or PINK1 in cultured neurons prevented this synapse loss, revealing a "sodium-PINK1" pathway that links neuronal activity to the targeted elimination of synapses.
