Biology subjects

Drerup, K.

Publications and source records attributed to Drerup, K..

4 recordsLinked to original sources

bioRxiv2025

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

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.

neuroscience↗

bioRxiv2025

Self-renewal of neuronal mitochondria through asymmetric division

Mitochondrial ATP production is essential for life. Mitochondrial function depends on the spatio-temporal coordination of nuclear and mitochondrial genome expression, yet how this coordination occurs in highly polarized cells such as neurons remains poorly understood. Using high-resolution imaging in mouse peripheral sensory neurons and zebrafish larvae, we identified a sub-population of mitochondria enriched in mtDNA that are positioned at the collateral branch points of long sensory neurites, both in vitro and in vivo. While the mitochondria in neurites are generally depleted of mtDNA, those at axon branch points preferentially engage in mtDNA replication and transcription, accumulate nuclear-encoded mitochondrial mRNA, and are spatially linked to nascent cytosolic peptide synthesis. The mtDNA-positive mitochondrial pool exhibits asymmetric genome partitioning at division, shedding highly motile daughters that lack mtDNA. Asymmetric division rejuvenates the membrane potential of the mtDNA-rich, biogenesis-dedicated mitochondria. We also found that, in peripheral sensory neurons, axonal mitochondria rarely fuse or share matrix contents, explaining how differentiated daughters maintain their distinct composition and fate after fission. Thus, division-coupled mitochondrial self-renewal is yoked to neurite topology in sensory neurons, patterning mitochondrial diversity and homeostasis from micron to meter scales.

cell biology↗

bioRxiv2025

Retrograde mitochondrial transport regulates mitochondrial biogenesis in zebrafish neurons

To maintain a functional mitochondrial population in a long-lived cell like a neuron, mitochondria must be continuously replenished through the process of mitochondrial biogenesis. Because most mitochondrial proteins are nuclear encoded, mitochondrial biogenesis requires communication between mitochondria and the nucleus. This can be a challenge in a large, compartmentalized cell like a neuron in which a large portion of the mitochondrial population is in neuronal compartments far from the nucleus. Using in vivo assessments of mitochondrial biogenesis in zebrafish neurons, we determined that mitochondrial transport between distal axonal compartments and the cell body is required for sustained mitochondrial biogenesis. Estrogen-related receptor transcriptional activation links transport with nuclear expression of mitochondrial genes. Together, our data support a role for retrograde feedback between axonal mitochondria and the nucleus for regulation of mitochondrial biogenesis in neurons.

neuroscience↗

bioRxiv2024

CCSer2 gates dynein activity at the cell periphery

Cytoplasmic dynein-1 (dynein) is a microtubule-associated, minus end-directed motor that traffics hundreds of different cargos. Dynein must discriminate between cargos and traffic them at the appropriate time from the correct cellular region. How dyneins trafficking activity is regulated in time or cellular space remains poorly understood. Here, we identify CCSer2 as the first known protein to gate dynein activity in the spatial dimension. CCSer2 promotes the migration of developing zebrafish primordium cells and of cultured human cells by facilitating the trafficking of cargos that are acted on by cortically localized dynein. CCSer2 inhibits the interaction between dynein and its regulator Ndel1 exclusively at the cell periphery, resulting in localized dynein activation. Our findings suggest that the spatial specificity of dynein is achieved by the localization of proteins that disinhibit Ndel1. We propose that CCSer2 defines a broader class of proteins that activate dynein in distinct microenvironments via Ndel1 inhibition.

cell biology↗