A physiological Na + signal activates mitochondrial PINK1 to couple synaptic depression to caspase-3-dependent spine pruning
Year: 2026
Type: preprint
Abstract: Mitochondrial density in dendrites adapts synaptic inputs to sustain local ATP and Ca 2+ 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.
Institutions: Max Planck Institute for Biological Intelligence, University of Stuttgart, University of Freiburg, University Medical Center Freiburg, German Cancer Research Center, Deutsches Konsortium für Translationale Krebsforschung, Munich Cluster for Systems Neurology, Technical University of Munich
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7163067803