Kinesin-1–syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport

Chen, Yanmin; Sheng, Zu‐Hang

doi:10.1083/jcb.201302040

Cited by 202 publications

(226 citation statements)

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“…GFP-labeled mitochondria in ALM neuronal processes appear as sphere and rod-shaped organelles of varying size distributed at distinct intervals (Fig. 1A), similar to axonal mitochondria in mammalian neurons (Kang et al, 2008;Chen and Sheng, 2013). Mitochondria in the adult neuronal cell bodies form a filamentous tubular network that encircles the soma perimeter (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…While the majority of mitochondria are stationary during a 5 min recording, some move along processes in a "stop and go" pattern ( Fig. 5A) similar to axonal mitochondria of mammalian and fly larvae neurons (Kang et al, 2008;Mondal et al, 2011;Chen and Sheng, 2013). Consistent with an ex vivo study in mouse nerve explants (Misgeld et al, 2007), we observed that motile mitochondria were significantly shorter than the stationary ones: the average length of motile mitochondria at 1DA is 1.1 Ϯ 0.4 m (mean Ϯ SEM; n ϭ 103), compared to 2.3 Ϯ 0.06 m when stationary (n ϭ 306, p Ͻ 0.01).…”

Section: Mitochondrial Trafficking In Distal Alm Process Declines Promentioning

confidence: 99%

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Age-Related Phasic Patterns of Mitochondrial Maintenance in AdultCaenorhabditis elegansNeurons

et al. 2016

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Aging is associated with cognitive decline and increasing risk of neurodegeneration. Perturbation of mitochondrial function, dynamics, and trafficking are implicated in the pathogenesis of several age-associated neurodegenerative diseases. Despite this fundamental importance, the critical understanding of how organismal aging affects lifetime neuronal mitochondrial maintenance remains unknown, particularly in a physiologically relevant context. To address this issue, we performed a comprehensive in vivo analysis of age-associated changes in mitochondrial morphology, density, trafficking, and stress resistance in individual Caenorhabditis elegans neurons throughout adult life. Adult neurons display three distinct stages of increase, maintenance, and decrease in mitochondrial size and density during adulthood. Mitochondrial trafficking in the distal neuronal processes declines progressively with age starting from early adulthood. In contrast, long-lived daf-2 mutants exhibit delayed age-associated changes in mitochondrial morphology, constant mitochondrial density, and maintained trafficking rates during adulthood. Reduced mitochondrial load at late adulthood correlates with decreased mitochondrial resistance to oxidative stress. Revealing aging-associated changes in neuronal mitochondria in vivo is an essential precedent that will allow future elucidation of the mechanistic causes of mitochondrial aging. Thus, our study establishes the critical foundation for the future analysis of cellular pathways and genetic and pharmacological factors regulating mitochondrial maintenance in aging-and disease-relevant conditions.

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Section: Resultsmentioning

confidence: 99%

Section: Mitochondrial Trafficking In Distal Alm Process Declines Promentioning

confidence: 99%

Age-Related Phasic Patterns of Mitochondrial Maintenance in AdultCaenorhabditis elegansNeurons

et al. 2016

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“…In support of this model, depletion of the Miro adaptor Trak1 is reported to decrease axonal branching (24). In addition, a specific kinase pathway was recently shown to support axon branching in cortical neurons by promoting immobilization of mitochondria at presynaptic sites via the docking protein syntaphilin (39,(46)(47)(48). Although the neuronal defects described here are the most likely cause of early mortality in Miro1 KO mice, changes in additional neuronal populations or tissues may also contribute to this phenotype.…”

Section: Discussionmentioning

confidence: 99%

Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease

Nguyen¹,

Weaver

et al. 2014

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

191

196

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Defective mitochondrial distribution in neurons is proposed to cause ATP depletion and calcium-buffering deficiencies that compromise cell function. However, it is unclear whether aberrant mitochondrial motility and distribution alone are sufficient to cause neurological disease. Calcium-binding mitochondrial Rho (Miro) GTPases attach mitochondria to motor proteins for anterograde and retrograde transport in neurons. Using two new KO mouse models, we demonstrate that Miro1 is essential for development of cranial motor nuclei required for respiratory control and maintenance of upper motor neurons required for ambulation. Neuron-specific loss of Miro1 causes depletion of mitochondria from corticospinal tract axons and progressive neurological deficits mirroring human upper motor neuron disease. Although Miro1-deficient neurons exhibit defects in retrograde axonal mitochondrial transport, mitochondrial respiratory function continues. Moreover, Miro1 is not essential for calcium-mediated inhibition of mitochondrial movement or mitochondrial calcium buffering. Our findings indicate that defects in mitochondrial motility and distribution are sufficient to cause neurological disease. Motor neuron diseases (MNDs), including ALS and spastic paraplegia (SP), are characterized by the progressive, lengthdependent degeneration of motor neurons, leading to muscle atrophy, paralysis, and, in some cases, premature death. There are both inherited and sporadic forms of MNDs, which can affect upper motor neurons, lower motor neurons, or both. Although the molecular and cellular causes of most MNDs are unknown, many are associated with defects in axonal transport of cellular components required for neuron function and maintenance (1-6).A subset of MNDs is associated with impaired mitochondrial respiration and mitochondrial distribution. This observation has led to the hypothesis that neurodegeneration results from defects in mitochondrial motility and distribution, which, in turn, cause subcellular ATP depletion and interfere with mitochondrial calcium ([Ca 2+ ] m ) buffering at sites of high synaptic activity (reviewed in ref. 7). It is not known, however, whether mitochondrial motility defects are a primary cause or a secondary consequence of MND progression. In addition, it has been difficult to isolate the primary effect of mitochondrial motility defects in MNDs because most mutations that impair mitochondrial motility in neurons also affect transport of other organelles and vesicles (1,(8)(9)(10)(11).In mammals, the movement of neuronal mitochondria between the cell body and the synapse is controlled by adaptors called trafficking kinesin proteins (Trak1 and Trak2) and molecular motors (kinesin heavy chain and dynein), which transport the organelle in the anterograde or retrograde direction along axonal microtubule tracks (7,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Mitochondrial Rho (Miro) GTPase proteins are critical for transport because they are the only known surface receptors that attach mitochondria to...

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“…In the second model, the KIF5 tail is linked to Miro1 via TRAK2 in a Ca 2 + -independent manner, freeing the motor domain to engage with microtubules. Ca 2 + binding to the EF-hand [40], (ii) KIF5 remains bound to the Miro1/TRAK2 complex upon uncoupling [55], or (iii) detachment from KIF5 occurs with subsequent interaction of the mitochondrial tether syntaphilin (SNPH) [61].…”

Section: Mitochondrial Trafficking In Astrocytic Processesmentioning

confidence: 99%

Mitochondrial dynamics in astrocytes

Stephen

Gupta‐Agarwal

Kittler

2014

Biochemical Society Transactions

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Astrocytes exhibit cellular excitability through variations in their intracellular calcium (Ca 2 + ) levels in response to synaptic activity. Astrocyte Ca 2 + elevations can trigger the release of neuroactive substances that can modulate synaptic transmission and plasticity, hence promoting bidirectional communication with neurons. Intracellular Ca 2 + dynamics can be regulated by several proteins located in the plasma membrane, within the cytosol and by intracellular organelles such as mitochondria. Spatial dynamics and strategic positioning of mitochondria are important for matching local energy provision and Ca 2 + buffering requirements to the demands of neuronal signalling. Although relatively unresolved in astrocytes, further understanding the role of mitochondria in astrocytes may reveal more about the complex bidirectional relationship between astrocytes and neurons in health and disease. In the present review, we discuss some recent insights regarding mitochondrial function, transport and turnover in astrocytes and highlight some important questions that remain to be answered.

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Kinesin-1–syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport

Abstract: Syntaphilin mediates the activity-dependent immobilization of axonal mitochondria by physically displacing KIF5 from the Miro–Trak transport complex.

Cited by 202 publications

References 44 publications

Age-Related Phasic Patterns of Mitochondrial Maintenance in AdultCaenorhabditis elegansNeurons

Age-Related Phasic Patterns of Mitochondrial Maintenance in AdultCaenorhabditis elegansNeurons

Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease

Mitochondrial dynamics in astrocytes

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