Abstract
Neurons are highly specialized cells with polarized cellular processes and subcellular domains. As vital organelles for neuronal functions, mitochondria are distributed by microtubule-based transport systems. Although the essential components of mitochondrial transport including motors and cargo adaptors are identified, it is less clear how mitochondrial distribution among somato-dendritic and axonal compartment is regulated. Here, we systematically study mitochondrial motors, including four kinesins, KIF5, KIF17, KIF1, KLP-6, and dynein, and transport regulators in C. elegans PVD neurons. Among all these motors, we found that mitochondrial export from soma to neurites is mainly mediated by KIF5/UNC-116. Interestingly, UNC-116 is especially important for axonal mitochondria, while dynein removes mitochondria from all plus-end dendrites and the axon. We surprisingly found one mitochondrial transport regulator for minus-end dendritic compartment, TRAK-1, and two mitochondrial transport regulators for axonal compartment, CRMP/UNC-33 and JIP3/UNC-16. While JIP3/UNC-16 suppresses axonal mitochondria, CRMP/UNC-33 is critical for axonal mitochondria; nearly no axonal mitochondria present in unc-33 mutants. We showed that UNC-33 is essential for organizing the population of UNC-116-associated microtubule bundles, which are tracks for mitochondrial trafficking. Disarrangement of these tracks impedes mitochondrial transport to the axon. In summary, we identified a compartment-specific transport regulation of mitochondria by UNC-33 through organizing microtubule tracks for different kinesin motors other than microtubule polarity.
Highlights
Neurons are polarized cells with functionally distinct cellular compartments including the somatodendritic and axonal compartments
We surprisingly found that Collapsin response mediator proteins (CRMPs)/UNC-33 is critical for axonal mitochondria and it supports a stable microtubule population to form a spindle-like structure in neuronal cell body as tracks for trafficking
We identified KIF5/UNC-116 as the main motor responsible for axonal mitochondria, which are strictly regulated by regulators; while JIP3/UNC-16 suppresses axonal mitochondria, CRMP2/ UNC-33 is essential for mitochondrial axonal distribution
Summary
Neurons are polarized cells with functionally distinct cellular compartments including the somatodendritic and axonal compartments. Apart from most other cells, the cellular processes of neurons are long. The axonal length of some motor neurons can be more than one meter long in mammals [1]. Neuronal functions demand a sound cellular transport system for distributing structural components, signaling molecules, and vital organelles. Mitochondria play multiple critical roles for neuron metabolism including the regulation of cell apoptosis, calcium ion reservoir, and energy supply. Defects of mitochondrial transport in neuron are implicated in many neurodegenerative diseases, including Huntington’s disease, amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease [6,7]. It is important to understand the mechanism of proper mitochondrial transport and distribution in neurons
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