A physiological Na+ signal activates mitochondrial PINK1 to couple synaptic depression to caspase-3-dependent spine pruning

Mitochondrial density in dendrites adapts synaptic inputs to sustain local ATP and Ca2+ buffering. During long-term depression (LTD), synapse elimination is accompanied by activation of caspase-3 through sublethal mitochondria-derived apoptotic signals. However, 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 PINK1 in a translation-dependent manner, leading to asynchronous mitochondrial fission. Na+ influx and PINK1 are required for cLTD-induced fission, and blocking either prevents caspase-3 activation and spine shrinking in cultured neurons. Together, these findings identify a Na+-PINK1 signaling 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