Motile Axonal Mitochondria Contribute to the Variability of Presynaptic Strength

Abstract

One 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, while 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 new insight into the fundamental properties of the CNS to ensure the plasticity and reliability of synaptic transmission.

Miro1‐dependent mitochondrial positioning drives the rescaling of presynaptic Ca 2+ signals during homeostatic plasticity

“…We hypothesise that increased expression of Miro1 makes mitochondria more likely to arrest close to presynaptic terminals in response to local Ca 2+ as Miro1 overexpression increases mitochondrial trafficking 13, 14, 33 and mitochondria pass terminals more frequently. Thus, even rare Ca 2+ responses during TTX treatment might be sufficient to allow mitochondrial arrest when Miro1 is overexpressed, and therefore, a higher percentage of terminals are always occupied by a mitochondrion.…”

Mitochondrial Dynamics in Visual Cortex Are Limited In Vivo and Not Affected by Axonal Structural Plasticity

“…Short-term plasticity is reduced [2,3,27] probably due to the Ca 2+ buffering capacity of mitochondria. Mitochondria passing by presynaptic boutons can cause changes in synaptic transmission [28]. The slow but continuous gain and loss of mitochondria at putative boutons we observed suggests that mitochondrion-induced synaptic effects will also occur in adult cortex but on a much slower timescale.…”

The Role of Mitochondrially Derived ATP in Synaptic Vesicle Recycling

“…Nonetheless, more sustained increases in energy demands may still preferentially deplete ATP from boutons lacking mitochondria. Indeed, after multiple rounds of electrical stimulation, Sun et al (55) found that the ATP/ADP ratio decreased more in boutons lacking mitochondria, despite having glucose present. In addition, we do not yet know whether regional energy failure between boutons also develops if the distance between mitochondria is pathologically increased (6).…”