Motile Axonal Mitochondria Contribute to the Variability of Presynaptic Strength

•Axonal mitochondrial motility correlates with the pulse-to-pulse EPSC variability•Motile mitochondria passing by boutons contribute to variation of SV release•Presynaptic mitochondria maintain SV release during sustained synaptic activity•Altered ATP homeostasis is one of the primary sources for presynaptic variability

SummaryOne of the most notable characteristics of synaptic transmission is the wide variation in synaptic strength in response to identical stimulation. In hippocampal neurons, approximately one-third of axonal mitochondria are highly motile, and some dynamically pass through presynaptic boutons. This raises a fundamental question: can motile mitochondria contribute to the pulse-to-pulse variability of presynaptic strength? Recently, we identified syntaphilin as an axonal mitochondrial-docking protein. Using hippocampal neurons and slices of syntaphilin knockout mice, we demonstrate that the motility of axonal mitochondria correlates with presynaptic variability. Enhancing mitochondrial motility increases the pulse-to-pulse variability, whereas immobilizing mitochondria reduces the variability. By dual-color live imaging at single-bouton levels, we further show that motile mitochondria passing through boutons dynamically influence synaptic vesicle release, mainly by altering ATP homeostasis in axons. Thus, our study provides insight into the fundamental properties of the CNS to ensure the plasticity and reliability of synaptic transmission.Video Abstract To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon belowHelp with MP4 filesOptionsDownload video (16145 K)

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