Science
A Na⁺-PINK1 signaling axis couples mitochondrial fission to structural remodeling during synaptic depression
Key Points
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.
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.