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bioRxiv · 10.64898/2025.12.26.696432

The combination of elevated neuronal activity and mitochondrial damage induces Pink1-dependent mitophagy in axons

Wisner, S. R.·Stein, C.·Smith, E. E.·Hoon, M.·Drerup, K.
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Abstract

Mitochondria are critical for synaptic function. At the synapse, mitochondria produce ATP and buffer calcium, both of which are required for synapse function. Defects in mitochondrial maintenance are linked to neurodegenerative disease, yet we know little about what regulates the need for mitophagy at the synapse. We assessed the impact of neuron type, activity, and mitochondrial damage on mitophagy rate in axons of larval zebrafish. Using electron and confocal microscopy, we show that mitophagy occurs in the axon terminal of postsynaptic sensory neurons and presynaptic motor neurons at similar rates. Increasing neuronal activity or mitochondria damage does not impact the amount of mitophagy in axons. Only by combining neuronal activity and mitochondrial damage does the rate of mitophagy increase in the axon and this increase requires Pink1. Together, our data support a model in which increased mitophagic demand in axons is rare and uniquely sensitive to Pink1 disruption.

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Wisner, S. R., Stein, C., Smith, E. E., Hoon, M., Drerup, K.. 2025-12-26. The combination of elevated neuronal activity and mitochondrial damage induces Pink1-dependent mitophagy in axons. https://doi.org/10.64898/2025.12.26.696432

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