Syntabulin-mediated anterograde transport of mitochondria along neuronal processes

Cai, Qian; Gerwin, Claudia; Sheng, Zu Hang

doi:10.1083/jcb.200506042

Cited by 197 publications

(191 citation statements)

References 49 publications

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“…Refs. [25][26][27] and for axons of cortical neurons (5). Similarly, the mean mitochondrial velocities were in agreement with published works, i.e.…”

Section: Trak2 Dn Reduces Mitochondrial Transport In Axons Ofsupporting

confidence: 81%

“…For example, the syntaxin-binding protein, syntabulin, is implicated in mitochondrial transport. In hippocampal neurons in culture, syntabulin co-localizes with mitochondria, it co-migrates with mitochondria along processes, and siRNA knockdown of syntabulin results in a significant reduction in the mitochondrial density in processes (26). Syntabulin utilizes the KIF5B motor (28), whereas TRAKs (both 1 and 2) co-immunoprecipitate from brain extracts predominantly with KIF5A (12).…”

Section: Discussionmentioning

confidence: 99%

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Trafficking Kinesin Protein (TRAK)-mediated Transport of Mitochondria in Axons of Hippocampal Neurons

Brickley

Stephenson

2011

Journal of Biological Chemistry

159

127

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In neurons, the proper distribution of mitochondria is essential because of a requirement for high energy and calcium buffering during synaptic neurotransmission. The efficient, regulated transport of mitochondria along axons to synapses is therefore crucial for maintaining function. The trafficking kinesin protein (TRAK)/Milton family of proteins comprises kinesin adaptors that have been implicated in the neuronal trafficking of mitochondria via their association with the mitochondrial protein Miro and kinesin motors. In this study, we used gene silencing by targeted shRNAi and dominant negative approaches in conjunction with live imaging to investigate the contribution of endogenous TRAKs, TRAK1 and TRAK2, to the transport of mitochondria in axons of hippocampal pyramidal neurons. We report that both strategies resulted in impairing mitochondrial mobility in axonal processes. Differences were apparent in terms of the contribution of TRAK1 and TRAK2 to this transport because knockdown of TRAK1 but not TRAK2 impaired mitochondrial mobility, yet both TRAK1 and TRAK2 were shown to rescue transport impaired by TRAK1 gene knock-out. Thus, we demonstrate for the first time the pivotal contribution of the endogenous TRAK family of kinesin adaptors to the regulation of mitochondrial mobility.Mitochondria serve several functions in cells. These functions include the generation of energy in the form of ATP, the buffering of calcium ions, and the regulation of apoptosis. Thus, within cells, mitochondria need to move so they can respond to local needs. In the nervous system, mitochondria and mitochondrial transport are particularly important because of a requirement for high energy and calcium buffering during synaptic neurotransmission. The mitochondrial population in neurons is therefore highly mobile, and the dynamics of their transport are tightly regulated to satisfy these demands. Mitochondria can move in both anterograde and retrograde directions, utilizing motor proteins and the microtubule network (for reviews, see Refs. 1-3). Furthermore, they can be anchored at defined sites; one example is mitochondrial immobilization by a Ca 2ϩ -dependent mechanism at synaptic sites (4 -7). Recently, there has been significant progress in the understanding of mitochondrial transport processes with the identification of several proteins implicated in their trafficking mechanisms.The best characterized of these include the trafficking kinesin protein (TRAK) 2 /Milton family of kinesin adaptors; Miro1 and Miro2, atypical Rho GTPases that reside in the mitochondrial outer membrane that are purported receptors for TRAKs; syntabulin, also a kinesin adaptor protein; and syntaphilin, an axonal mitochondrial docking protein (for reviews, see Refs. 3 and 8).There are two mammalian TRAKs, TRAK1 and TRAK2, that share ϳ58% amino acid homology (9, 10). The TRAKs, like their Drosophila orthologue Milton (11), have been shown to function as kinesin adaptors linking kinesin heavy chain (KHC) to mitochondria by their association with Miro1/2. T...

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“…Refs. [25][26][27] and for axons of cortical neurons (5). Similarly, the mean mitochondrial velocities were in agreement with published works, i.e.…”

Section: Trak2 Dn Reduces Mitochondrial Transport In Axons Ofsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Trafficking Kinesin Protein (TRAK)-mediated Transport of Mitochondria in Axons of Hippocampal Neurons

Brickley

Stephenson

2011

Journal of Biological Chemistry

159

127

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“…Consistent with a role for KIF5B on dysferlin-containing vesicles, live-cell imaging of L6 myotubes expressing dysferlin-mCh and eGFP-KIF5B revealed that dysferlin-containing vesicles are labeled by KIF5B, and co-labeled vesicles are capable of long-range movements. Furthermore, the measured velocity of motile dysferlin-containing vesicles is in the range of velocities reported for mitochondria in neurons (34), and kinesin motors in COS cells (35). Interestingly, most KIF5B labeled dysferlin-containing vesicles did not show long-range processive movement and are limited to local movements in resting L6 myotubes.…”

Section: Dysferlin-containing Vesicles Move Along Microtubules Via Kimentioning

confidence: 68%

Membrane damage-induced vesicle–vesicle fusion of dysferlin-containing vesicles in muscle cells requires microtubules and kinesin

McDade

Michele

2013

Human Molecular Genetics

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Mutations in the dysferlin gene resulting in dysferlin-deficiency lead to limb-girdle muscular dystrophy 2B and Myoshi myopathy in humans. Dysferlin has been proposed as a critical regulator of vesicle-mediated membrane resealing in muscle fibers, and localizes to muscle fiber wounds following sarcolemma damage. Studies in fibroblasts and urchin eggs suggest that trafficking and fusion of intracellular vesicles with the plasma membrane during resealing requires the intracellular cytoskeleton. However, the contribution of dysferlin-containing vesicles to resealing in muscle and the role of the cytoskeleton in regulating dysferlin-containing vesicle biology is unclear. Here, we use live-cell imaging to examine the behavior of dysferlin-containing vesicles following cellular wounding in muscle cells and examine the role of microtubules and kinesin in dysferlin-containing vesicle behavior following wounding. Our data indicate that dysferlin-containing vesicles move along microtubules via the kinesin motor KIF5B in muscle cells. Membrane wounding induces dysferlin-containing vesicle-vesicle fusion and the formation of extremely large cytoplasmic vesicles, and this response depends on both microtubules and functional KIF5B. In non-muscle cell types, lysosomes are critical mediators of membrane resealing, and our data indicate that dysferlincontaining vesicles are capable of fusing with lysosomes following wounding which may contribute to formation of large wound sealing vesicles in muscle cells. Overall, our data provide mechanistic evidence that microtubulebased transport of dysferlin-containing vesicles may be critical for resealing, and highlight a critical role for dysferlin-containing vesicle-vesicle and vesicle-organelle fusion in response to wounding in muscle cells.

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“…We specifically focused on Kif5C and Kif3A kinesin complexes and have identified several proteins that are potentially targeted to synapses. Previous studies identified some cargos of Kif5C, including GABA receptors (22), axonal synaptic vesicle precursors (23), APP-containing vesicles (24,25), TrkB vesicles (26), mitochondria (23,(27)(28)(29)(30)(31), AMPAR vesicles (32), and mRNA/protein complexes (33,34). Kif3 was shown to transport fodrin-associating vesicles in cultured superior cervical ganglion neurons (35), Ncadherin in the developing mouse brain (36) and axonal voltagegated potassium channel in cultured hippocampal neurons (37).…”

Section: Discussionmentioning

confidence: 99%

New approach to capture and characterize synaptic proteome

Liu¹,

Kadakkuzha²,

Pascal³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Little is known regarding the identity of the population of proteins that are transported and localized to synapses. Here we describe a new approach that involves the isolation and systematic proteomic characterization of molecular motor kinesins to identify the populations of proteins transported to synapses. We used this approach to identify and compare proteins transported to synapses by kinesin (Kif) complexes Kif5C and Kif3A in the mouse hippocampus and prefrontal cortex. Approximately 40-50% of the protein cargos identified in our proteomics analysis of kinesin complexes are known synaptic proteins. We also found that the identity of kinesins and where they are expressed determine what proteins they transport. Our results reveal a previously unappreciated role of kinesins in regulating the composition of synaptic proteome.kinesin | protein transport | synapse | proteome | hippocampus

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Syntabulin-mediated anterograde transport of mitochondria along neuronal processes

Cited by 197 publications

References 49 publications

Trafficking Kinesin Protein (TRAK)-mediated Transport of Mitochondria in Axons of Hippocampal Neurons

Trafficking Kinesin Protein (TRAK)-mediated Transport of Mitochondria in Axons of Hippocampal Neurons

Membrane damage-induced vesicle–vesicle fusion of dysferlin-containing vesicles in muscle cells requires microtubules and kinesin

New approach to capture and characterize synaptic proteome

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