Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration (original) (raw)

• Nicholls, D. G. & Budd, S. L. Mitochondria and neuronal survival. Physiol. Rev. 80, 315–360 (2000).
  Article CAS PubMed Google Scholar
• Verstreken, P. et al. Synaptic mitochondria are critical for mobilization of reserve pool vesicles at Drosophila neuromuscular junctions. Neuron 47, 365–378 (2005). This paper shows that in D. melanogaster with mutant DRP1, the loss of mitochondria from neuromuscular junctions results in faster depletion of synaptic vesicles during prolonged pulse train stimulation owing to a specific defect in mobilizing reserve pool vesicles.
  Article CAS PubMed Google Scholar
• Lee, C. W. & Peng, H. B. The function of mitochondria in presynaptic development at the neuromuscular junction. Mol. Biol. Cell 19, 150–158 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Attwell, D. & Laughlin, S. B. An energy budget for signaling in the grey matter of the brain. J. Cereb. Blood Flow Metab. 21, 1133–1145 (2001).
  Article CAS PubMed Google Scholar
• Werth, J. L. & Thayer, S. A. Mitochondria buffer physiological calcium loads in cultured rat dorsal root ganglion neurons. J. Neurosci. 14, 348–356 (1994).
  Article CAS PubMed PubMed Central Google Scholar
• Tang, Y. & Zucker, R. S. Mitochondrial involvement in post-tetanic potentiation of synaptic transmission. Neuron 18, 483–491 (1997).
  Article CAS PubMed Google Scholar
• Billups, B. & Forsythe, I. D. Presynaptic mitochondrial calcium sequestration influences transmission at mammalian central synapses. J. Neurosci. 22, 5840–5847 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Medler, K. & Gleason, E. L. Mitochondrial Ca2+ buffering regulates synaptic transmission between retinal amacrine cells. J. Neurophysiol. 87, 1426–1439 (2002).
  Article CAS PubMed Google Scholar
• David, G. & Barrett, E. F. Mitochondrial Ca2+ uptake prevents desynchronization of quantal release and minimizes depletion during repetitive stimulation of mouse motor nerve terminals. J. Physiol. 548, 425–438 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Talbot, J. D., David, G. & Barrett, E. F. Inhibition of mitochondrial Ca2+ uptake affects phasic release from motor terminals differently depending on external [Ca2+]. J. Neurophysiol. 90, 491–502 (2003).
  Article CAS PubMed Google Scholar
• Levy, M., Faas, G. C., Saggau, P., Craigen, W. J. & Sweatt, J. D. Mitochondrial regulation of synaptic plasticity in the hippocampus. J. Biol. Chem. 278, 17727–17734 (2003).
  Article CAS PubMed Google Scholar
• Kang, J. S. et al. Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation. Cell 132, 137–148 (2008). By using genetic mouse models and time-lapse imaging this study identifies syntaphilin as a 'static anchor' for axonal mitochondria.
  Article CAS PubMed PubMed Central Google Scholar
• Hollenbeck, P. J. & Saxton, W. M. The axonal transport of mitochondria. J. Cell Sci. 118, 5411–5419 (2005).
  Article CAS PubMed Google Scholar
• Bogan, N. & Cabot, J. B. Light and electron microscopic analyses of intraspinal axon collaterals of sympathetic preganglionic neurons. Brain Res. 541, 241–251 (1991).
  Article CAS PubMed Google Scholar
• Fabricius, C., Berthold, C. H. & Rydmark, M. Axoplasmic organelles at nodes of Ranvier. II. Occurrence and distribution in large myelinated spinal cord axons of the adult cat. J. Neurocytol. 22, 941–954 (1993).
  Article CAS PubMed Google Scholar
• Morris, R. L. & Hollenbeck, P. J. The regulation of bidirectional mitochondrial transport is coordinated with axonal outgrowth. J. Cell Sci. 104, 917–927 (1993).
  PubMed Google Scholar
• Mutsaers, S. E. & Carroll, W. M. Focal accumulation of intra-axonal mitochondria in demyelination of the cat optic nerve. Acta Neuropathol. 96, 139–143 (1998).
  Article CAS PubMed Google Scholar
• Ruthel, G. & Hollenbeck, P. J. Response of mitochondrial traffic to axon determination and differential branch growth. J. Neurosci. 23, 8618–8624 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Li, Z., Okamoto, K., Hayashi, Y. & Sheng, M. The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119, 873–887 (2004).
  Article CAS PubMed Google Scholar
• Zhang, C. L., Ho, P. L., Kintner, D. B., Sun, D. & Chiu, S. Y. Activity-dependent regulation of mitochondrial motility by calcium and Na/K-ATPase at nodes of Ranvier of myelinated nerves. J. Neurosci. 30, 3555–3566 (2010). This study demonstrates a highly localized elevation of axonal Ca 2+ levels and reduced mitochondrial mobility at individual nodes of Ranvier during a brief train of action potentials.
  Article CAS PubMed PubMed Central Google Scholar
• Amiri, M. & Hollenbeck, P. J. Mitochondrial biogenesis in the axons of vertebrate peripheral neurons. Dev. Neurobiol. 68, 1348–1361 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Rintoul, G. L., Filiano, A. J., Brocard, J. B., Kress, G. J. & Reynolds, I. J. Glutamate decreases mitochondrial size and movement in primary forebrain neurons. J. Neurosci. 23, 7881–7888 (2003). This study shows that mobile mitochondria are recruited to stationary pools in response to acute application of glutamate to cultured neurons. Mitochondria are also changed from an elongated to a rounded morphology.
  Article CAS PubMed PubMed Central Google Scholar
• Macaskill, A. F. et al. Miro1 is a calcium sensor for glutamate receptor-dependent localization of mitochondria at synapses. Neuron 61, 541–555 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, X. & Schwarz, T. L. The mechanism of Ca2+-dependent regulation of kinesin-mediated mitochondrial motility. Cell 136, 163–174 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Saotome, M. et al. Bidirectional Ca2+-dependent control of mitochondrial dynamics by the Miro GTPase. Proc. Natl Acad. Sci. USA 105, 20728–20733 (2008). References 23, 24 and 25 independently identified MIRO as a Ca 2+ sensor, providing a mechanism for the underlying Ca 2+ -dependent regulation of mitochondrial mobility.
  Article CAS PubMed PubMed Central Google Scholar
• Yi, M., Weaver, D. & Hajnóczky, G. Control of mitochondrial motility and distribution by the calcium signal: a homeostatic circuit. J. Cell Biol. 167, 661–672 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Chang, D. T. & Reynolds, I. J. Mitochondrial trafficking and morphology in healthy and injured neurons. Prog. Neurobiol. 80, 241–268 (2006).
  Article CAS PubMed Google Scholar
• Chan, D. C. Mitochondria: dynamic organelles in disease, aging, and development. Cell 125, 1241–1252 (2006).
  Article CAS PubMed Google Scholar
• Stokin, G. B. & Goldstein, L. S. Axonal transport and Alzheimer's disease. Annu. Rev. Biochem. 75, 607–627 (2006).
  Article CAS PubMed Google Scholar
• Schon, E. A. & Przedborski, S. Mitochondria: the next (neurode) generation. Neuron 70, 1033–1053 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Miller, K. E. & Sheetz, M. P. Direct evidence for coherent low velocity axonal transport of mitochondria. J. Cell Biol. 173, 373–381 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Misgeld, T., Kerschensteiner, M., Bareyre, F. M., Burgess, R. W. & Lichtman, J. W. Imaging axonal transport of mitochondria in vivo. Nature Methods 4, 559–561 (2007). This study develops an elegant tool to visualize axonal mitochondrial transport in living mice and explanted nervous tissue.
  Article CAS PubMed Google Scholar
• Hirokawa, N., Niwa, S. & Tanaka, Y. Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease. Neuron 68, 610–638 (2010).
  Article CAS PubMed Google Scholar
• Martin, M. et al. Cytoplasmic dynein, the dynactin complex, and kinesin are interdependent and essential for fast axonal transport. Mol. Biol. Cell 10, 3717–3728 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Tanaka, Y. et al. Targeted disruption of mouse conventional kinesin heavy chain, kif5B, results in abnormal perinuclear clustering of mitochondria. Cell 93, 1147–1158 (1998). This is the first genetic mouse study showing that KIF5 motors are essential for mitochondrial transport.
  Article CAS PubMed Google Scholar
• Górska-Andrzejak, J. et al. Mitochondria are redistributed in Drosophila photoreceptors lacking milton, a kinesin-associated protein. J. Comp. Neurol. 463, 372–388 (2003).
  Article CAS PubMed Google Scholar
• Pilling, A. D., Horiuchi, D., Lively, C. M. & Saxton, W. M. Kinesin-1 and Dynein are the primary motors for fast transport of mitochondria in Drosophila motor axons. Mol. Biol. Cell 17, 2057–2068 (2006). This study provides the genetic evidence in the D. melanogaster nervous system that dynein motors have a crucial role in mitochondrial retrograde transport in axons.
  Article CAS PubMed PubMed Central Google Scholar
• MacAskill, A. F. & Kittler, J. T. Control of mitochondrial transport and localization in neurons. Trends Cell Biol. 20, 102–112 (2010).
  Article CAS PubMed Google Scholar
• Kanai, Y. et al. KIF5C, a novel neuronal kinesin enriched in motor neurons. J. Neurosci. 20, 6374–6384 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Hirokawa, N. et al. Kinesin associates with anterogradely transported membranous organelles in vivo. J. Cell Biol. 114, 295–302 (1991). This study shows that KIF5 motors are attached to brain mitochondria.
  Article CAS PubMed Google Scholar
• Cai, Q., Gerwin, C. & Sheng, Z.-H. Syntabulin-mediated anterograde transport of mitochondria along neuronal processes. J. Cell Biol. 170, 959–969 (2005). This study identifies syntabulin as a second prominent KIF5 motor adaptor for mitochondria. Syntabulin loss-of-function or interference of the syntaphilin–KIF5 interaction reduces anterograde, but not retrograde, mitochondrial transport along axons.
  Article CAS PubMed PubMed Central Google Scholar
• Nangaku, M. et al. KIF1B, a novel microtubule plus end-directed monomeric motor protein for transport of mitochondria. Cell 79, 1209–1220 (1994).
  Article CAS PubMed Google Scholar
• Tanaka, K., Sugiura, Y., Ichishita, R., Mihara, K. & Oka, T. KLP6: a newly identified kinesin that regulates the morphology and transport of mitochondria in neuronal cells. J. Cell Sci. 124, 2457–2465 (2011).
  Article CAS PubMed Google Scholar
• Stowers, R. S., Megeath, L. J., Górska-Andrzejak, J., Meinertzhagen, I. A. & Schwarz, T. L. Axonal transport of mitochondria to synapses depends on milton, a novel Drosophila protein. Neuron 36, 1063–1077 (2002). This paper reports that D. melanogaster photoreceptors that express mutant Milton show aberrant synaptic transmission owing to a reduced distribution of mitochondria at synapses.
  Article CAS PubMed Google Scholar
• Fransson, A., Ruusala, A. & Aspenström, P. Atypical Rho GTPases have roles in mitochondrial homeostasis and apoptosis. J. Biol. Chem. 278, 6495–6502 (2003).
  Article CAS PubMed Google Scholar
• Fransson, S., Ruusala, A. & Aspenström, P. The atypical Rho GTPases Miro-1 and Miro-2 have essential roles in mitochondrial trafficking. Biochem. Biophys. Res. Commun. 344, 500–510 (2006).
  Article CAS PubMed Google Scholar
• Frederick, R. L., McCaffery, J. M., Cunningham, K. W., Okamoto, K. & Shaw, J. M. Yeast Miro GTPase, Gem1p, regulates mitochondrial morphology via a novel pathway. J. Cell Biol. 167, 87–98 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Glater, E. E., Megeath, L. J., Stowers, R. S. & Schwarz, T. L. Axonal transport of mitochondria requires milton to recruit kinesin heavy chain and is light chain independent. J. Cell Biol. 173, 545–557 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Guo, X. et al. The GTPase dMiro is required for axonal transport of mitochondria to Drosophila synapses. Neuron 47, 379–393 (2005). In this paper, the authors show that a MIRO mutant results in the chronic loss of mitochondria from neuromuscular junctions, a reduction in Ca 2+ buffering capacity and impaired neurotransmitter release during prolonged stimulation.
  Article CAS PubMed Google Scholar
• Brickley, K., Smith, M. J., Beck, M. & Stephenson, F. A. GRIF-1 and OIP106, members of a novel gene family of coiled-coil domain proteins: association in vivo and in vitro with kinesin. J. Biol. Chem. 280, 14723–14732 (2005).
  Article CAS PubMed Google Scholar
• Smith, M. J., Pozo, K., Brickley, K. & Stephenson, F. A. Mapping the GRIF-1 binding domain of the kinesin, KIF5C, substantiates a role for GRIF-1 as an adaptor protein in the anterograde trafficking of cargoes. J. Biol. Chem. 281, 27216–27228 (2006).
  Article CAS PubMed Google Scholar
• Grishin, A., Li, H., Levitan, E. S. & Zaks-Makhina, E. Identification of γ-aminobutyric acid receptor-interacting factor 1 (TRAK2) as a trafficking factor for the K+ channel Kir2.1. J. Biol. Chem. 281, 30104–30111 (2006).
  Article CAS PubMed Google Scholar
• Kirk, E., Chin, L. S. & Li, L. GRIF1 binds Hrs and is a new regulator of endosomal trafficking. J. Cell Sci. 119, 4689–4701 (2006).
  Article CAS PubMed Google Scholar
• Webber, E., Li, L. & Chin, L. S. Hypertonia-associated protein Trak1 is a novel regulator of endosome-to-lysosome trafficking. J. Mol. Biol. 382, 638–651 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• MacAskill, A. F., Brickley, K., Stephenson, F. A. & Kittler, J. T. GTPase dependent recruitment of Grif-1by Miro1 regulates mitochondrial trafficking in hippocampal neurons. Mol. Cell. Neurosci. 40, 301–312 (2009).
  Article CAS PubMed Google Scholar
• Brickley, K. & Stephenson, F. A. Trafficking kinesin protein (TRAK)-mediated transport of mitochondria in axons of hippocampal neurons. J. Biol. Chem. 286, 18079–18092 (2011). References 55 and 56 provide evidence that elevating MIRO1 levels enhances the recruitment of the TRAK2–KIF5 transport complex to mitochondria and that knocking down TRAK1 or expressing dominant-negative TRAK1 mutants results in impaired mitochondrial mobility in axons.
  Article CAS PubMed PubMed Central Google Scholar
• Ikuta, J. et al. Fasciculation and elongation protein zeta-1 (FEZ1) participates in the polarization of hippocampal neuron by controlling the mitochondrial motility. Biochem. Biophys. Res. Commun. 353, 127–132 (2007).
  Article CAS PubMed Google Scholar
• Fujita T. et al. Axonal guidance protein FEZ1 associates with tubulin and kinesin motor protein to transport mitochondria in neurites of NGF-stimulated PC12 cells. Biochem. Biophys. Res. Commun. 361, 605–610 (2007).
  Article CAS PubMed Google Scholar
• Cho, K. I. et al. Association of the kinesin-binding domain of RanBP2 to KIF5B and KIF5C determines mitochondria localization and function. Traffic 8, 1722–1735 (2007).
  Article CAS PubMed Google Scholar
• Schwarzer, C., Barnikol-Watanabe, S., Thinnes, F. P. & Hilschmann, N. Voltage-dependent anion-selective channel (VDAC) interacts with the dynein light chain Tctex1 and the heat-shock protein PBP74. Int. J. Biochem. Cell Biol. 34, 1059–1070 (2002).
  Article CAS PubMed Google Scholar
• King, S. J. & Schroer, T. A. Dynactin increases the processivity of the cytoplasmic dynein motor. Nature Cell Biol. 2, 20–24 (2000).
  Article CAS PubMed Google Scholar
• Haghnia, M. et al. Dynactin is required for coordinated bidirectional motility, but not for dynein membrane attachment. Mol. Biol. Cell 18, 2081–2089 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Cai, Q. et al. Snapin-regulated late endosomal transport is critical for efficient autophagy-lysosomal function in neurons. Neuron 68, 73–86 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Russo, G. J. et al. Drosophila Miro is required for both anterograde and retrograde axonal mitochondrial transport. J. Neurosci. 29, 5443–5455 (2009). This study suggests that MIRO promotes either kinesin- or dynein-mediated movement during a neuronal signal that dictates the net transport direction of mitochondria.
  Article CAS PubMed PubMed Central Google Scholar
• Hirokawa, N., Sato-Yoshitake, R., Yoshida, T. & Kawashima, T. Brain dynein (MAP1C) localizes on both anterogradely and retrogradely transported membranous organelles in vivo. J. Cell Biol. 111, 1027–1037 (1990).
  Article CAS PubMed Google Scholar
• Ligon, L. A., Tokito, M., Finklestein, J. M., Grossman, F. E. & Holzbaur, E. L. A direct interaction between cytoplasmic dynein and kinesin I may coordinate motor activity. J. Biol. Chem. 279, 19201–19208 (2004).
  Article CAS PubMed Google Scholar
• Welte, M. A. Bidirectional transport along microtubules. Curr. Biol. 14, R525–R537 (2004).
  Article CAS PubMed Google Scholar
• Mallik, R., Petrov, D., Lex, S. A., King, S. J. & Gross, S. P. Building complexity: an in vitro study of cytoplasmic dynein with in vivo implications. Curr. Biol. 15, 2075–2085 (2005).
  Article CAS PubMed Google Scholar
• Horiuchi, D., Barkus, R. V., Pilling, A. D., Gassman, A. & Saxton, W. M. APLIP1, a kinesin binding JIP-1/JNK scaffold protein, influences the axonal transport of both vesicles and mitochondria in Drosophila. Curr. Biol. 15, 2137–2141 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Misko, A., Jiang, S., Wegorzewska, I., Milbrandt, J. & Baloh, R. H. Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex. J. Neurosci. 30, 4232–4240 (2010). This study highlights a role of the MIRO2–MFN2 complex in regulating the processivity of kinesin or in coordinating the switch between kinesin and dynein.
  Article CAS PubMed PubMed Central Google Scholar
• Morris, R. L. & Hollenbeck, P. J. Axonal transport of mitochondria along microtubules and F-actin in living vertebrate neurons. J. Cell Biol. 131, 1315–1326 (1995).
  Article CAS PubMed Google Scholar
• Quintero, O. A. et al. Human Myo19 is a novel myosin that associates with mitochondria. Curr. Biol. 19, 2008–2013 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Naisbitt, S. et al. Interaction of the postsynaptic density-95/guanylate kinase domain-associated protein complex with a light chain of myosin-V and dynein. J. Neurosci. 20, 4524–4534 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Chada, S. R. & Hollenbeck, P. J. Nerve growth factor signaling regulates motility and docking of axonal mitochondria. Curr. Biol. 14, 1272–1276 (2004).
  Article CAS PubMed Google Scholar
• Pathak, D., Sepp, K. J. & Hollenbeck, P. J. Evidence that myosin activity opposes microtubule-based axonal transport of mitochondria. J. Neurosci. 30, 8984–8992 (2010). References 74 and 75 provide compelling evidence that NGF can regulate mitochondrial mobility by influencing static interactions between mitochondria and actin and that inhibiting actin-based myosin motors results in increased mitochondrial mobility.
  Article CAS PubMed PubMed Central Google Scholar
• Hubley, M. J., Locke, B. R. & Moerland, T. S. The effects of temperature, pH, and magnesium on the diffusion coefficient of ATP in solutions of physiological ionic strength. Biochim. Biophys. Acta 1291, 115–121 (1996).
  Article PubMed Google Scholar
• Hirokawa, N. Cross-linker system between neurofilaments, microtubules, and membranous organelles in frog axons revealed by the quick-freeze, deep-etching method. J. Cell Biol. 94, 129–142 (1982). This study provides the first morphological evidence for the crossbridges between axonal mitochondria and microtubules or neurofilaments.
  Article CAS PubMed PubMed Central Google Scholar
• Lindén, M., Nelson, B. D., Loncar, D. & Leterrier, J. F. Studies on the interaction between mitochondria and the cytoskeleton. J. Bioenerg. Biomembr. 21, 507–518 (1989).
  Article PubMed Google Scholar
• Jung, D., Filliol, D., Miehe, M. & Rendon, A. Interaction of brain mitochondria with microtubules reconstituted from brain tubulin and MAP2 or TAU. Cell Motil. Cytoskeleton 24, 245–255 (1993).
  Article CAS PubMed Google Scholar
• Price, R. L., Lasek, R. J. & Katz, M. J. Microtubules have special physical associations with smooth endoplasmic reticula and mitochondria in axons. Brain Res. 540, 209–216 (1991).
  Article CAS PubMed Google Scholar
• Chen, Y. M., Gerwin, C. & Sheng, Z.-H. Dynein light chain LC8 regulates syntaphilin-mediated mitochondrial docking in axons. J. Neurosci. 29, 9429–9438 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Sung, J. Y. et al. WAVE1 controls neuronal activity-induced mitochondrial distribution in dendritic spines. Proc. Natl Acad. Sci. USA. 105, 3112–3116 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Wagner, O. I. et al. Mechanisms of mitochondria-neurofilament interactions. J. Neurosci. 23, 9046–9058 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Mironov, S. L. ADP regulates movements of mitochondria in neurons. Biophys. J. 92, 2944–2952 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Chang, D. T., Honick, A. S. & Reynolds, I. J. Mitochondrial trafficking to synapses in cultured primary cortical neurons. J. Neurosci. 26, 7035–7045 (2006). This study demonstrates that mitochondrial mobility is regulated in response to changes in synaptic activity.
  Article CAS PubMed PubMed Central Google Scholar
• Cai, Q. & Sheng, Z. H. Moving or stopping mitochondria: Miro as a traffic cop by sensing calcium. Neuron 61, 493–496 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Chang, K. T., Niescier, R. F. & Min, K. T. Mitochondrial matrix Ca2+ as an intrinsic signal regulating mitochondrial motility in axons. Proc. Natl Acad. Sci. USA 108, 15456–15461 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Han, X. J. et al. CaM kinase I α-induced phosphorylation of Drp1 regulates mitochondrial morphology. J. Cell Biol. 182, 573–585 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, S., Owens, G. C., Crossin, K. L. & Edelman, D. B. Serotonin stimulates mitochondrial transport in hippocampal neurons. Mol. Cell. Neurosci. 36, 472–483 (2007).
  Article CAS PubMed Google Scholar
• Chen, S. et al. Dopamine inhibits mitochondrial motility in hippocampal neurons. PLoS ONE 3, e2804 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Rintoul, G. L., Bennett, V. J., Papaconstandinou, N. A. & Reynolds, I. J. Nitric oxide inhibits mitochondrial movement in forebrain neurons associated with disruption of mitochondrial membrane potential. J. Neurochem. 97, 800–806 (2006).
  Article CAS PubMed Google Scholar
• Zanelli, S. A. et al. Nitric oxide impairs mitochondrial movement in cortical neurons during hypoxia. J. Neurochem. 97, 724–736 (2006).
  Article CAS PubMed Google Scholar
• Stamer, K., Vogel, R., Thies, E., Mandelkow, E. & Mandelkow, E. M. Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J. Cell Biol. 156, 1051–1063 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Dubey, M., Chaudhury, P., Kabiru, H. & Shea, T. B. Tau inhibits anterograde axonal transport and perturbs stability in growing axonal neurites in part by displacing kinesin cargo: neurofilaments attenuate tau-mediated neurite instability. Cell Motil. Cytoskeleton 65, 89–99 (2008).
  Article CAS PubMed Google Scholar
• Stoothoff, W. et al. Differential effect of three-repeat and four-repeat tau on mitochondrial axonal transport. J. Neurochem. 111, 417–427 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Trinczek, B., Ebneth, A., Mandelkow, E. M. & Mandelkow, E. Tau regulates the attachment/detachment but not the speed of motors in microtubule-dependent transport of single vesicles and organelles. J. Cell Sci. 112, 2355–2367 (1999).
  CAS PubMed Google Scholar
• Mandelkow, E. M., Thies, E., Trinczek, B., Biernat, J. & Mandelkow, E. MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons. J. Cell Biol. 167, 99–110 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Vossel, K. A. et al. Tau reduction prevents Aβ-induced defects in axonal transport. Science 330, 198 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Dixit, R., Ross, J. L., Goldman, Y. E. & Holzbaur, E. L. Differential regulation of dynein and kinesin motor proteins by tau. Science 319, 1086–1089 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Jiménez-Mateos, E. M., González-Billault, C., Dawson, H. N., Vitek, M. P. & Avila, J. Role of MAP1B in axonal retrograde transport of mitochondria. Biochem. J. 397, 53–59 (2006).
  Article PubMed PubMed Central Google Scholar
• Ohno, N. et al. Myelination and axonal electrical activity modulate the distribution and motility of mitochondria at CNS nodes of Ranvier. J. Neurosci. 31, 7249–7258 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Craner, M. J. et al. Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. Proc. Natl Acad. Sci. USA 101, 8168–8173 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Andrews, H. et al. Increased axonal mitochondrial activity as an adaptation to myelin deficiency in the Shiverer mouse. J. Neurosci. Res. 83, 1533–1539 (2006).
  Article CAS PubMed Google Scholar
• Hogan, V. et al. Increase in mitochondrial density within axons and supporting cells in response to demyelination in the Plp1 mouse model. J. Neurosci. Res. 87, 452–459 (2009).
  Article CAS PubMed Google Scholar
• Kiryu-Seo, S., Ohno, N., Kidd, G. J., Komuro, H. & Trapp, B. D. Demyelination increases axonal stationary mitochondrial size and the speed of axonal mitochondrial transport. J. Neurosci. 30, 6658–6666 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Shepherd, G. M. & Harris, K. M. Three-dimensional structure and composition of CA3-CA1 axons in rat hippocampal slices: implications for presynaptic connectivity and compartmentalization. J. Neurosci. 18, 8300–8310 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Rowland, K. C., Irby, N. K. & Spirou, G. A. Specialized synapse-associated structures within the calyx of Held. J. Neurosci. 20, 9135–9144 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Ma, H., Cai, Q., Lu, W., Sheng, Z.-H. & Mochida, S. KIF5B motor adaptor syntabulin maintains synaptic transmission in sympathetic neurons. J. Neurosci. 29, 13019–13029 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Gross, N. J., Getz, G. S. & Rabinowitz, M. Apparent turnover of mitochondrial deoxyribonucleic acid and mitochondrial phospholipids in the tissues of the rat. J. Biol. Chem. 244, 1552–1562 (1969).
  CAS PubMed Google Scholar
• Menzies, R. A. & Gold, P. H. The turnover of mitochondria in a variety of tissues of young adult and aged rats. J. Biol. Chem. 246, 2425–2429 (1971).
  CAS PubMed Google Scholar
• Chen, H. & Chan, D. C. Mitochondrial dynamics — fusion, fission, movement, and mitophagy — in neurodegenerative diseases. Hum. Mol. Genet. 18, 169–176 (2009).
  Article CAS Google Scholar
• Ishihara, N. et al. Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nature Cell Biol. 11, 958–966 (2009).
  Article CAS PubMed Google Scholar
• Liu, X. & Hajnoczky, G. Ca2+-dependent regulation of mitochondrial dynamics by the Miro–Milton complex. Int. J. Biochem . Cell Biol. 41, 1972–1976 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Varadi, A. et al. Cytoplasmic dynein regulates the subcellular distribution of mitochondria by controlling the recruitment of the fission factor dynamin-related protein-1. J. Cell Sci. 117, 4389–4400 (2004).
  Article CAS PubMed Google Scholar
• Baloh, R. H., Schmidt, R. E., Pestronk, A. & Milbrandt, J. Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. J. Neurosci. 27, 422–430 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, H. et al. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J. Cell Biol. 160, 189–200 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Detmer, S. A., Vande Velde, C., Cleveland, D. W. & Chan, D. C. Hindlimb gait defects due to motor axon loss and reduced distal muscles in a transgenic mouse model of Charcot-Marie-Tooth type 2A. Hum. Mol. Genet. 17, 367–375 (2008).
  Article CAS PubMed Google Scholar
• Chen, H., McCaffery, J. M. & Chan, D. C. Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 130, 548–562 (2007).
  Article CAS PubMed Google Scholar
• Weihofen, A. et al. Pink1 forms a multiprotein complex with Miro and Milton, linking Pink1 function to mitochondrial trafficking. Biochemistry 48, 2045–2052 (2009).
  Article CAS PubMed Google Scholar
• Yu, W., Sun, Y., Guo, S. & Lu, B. The PINK1/Parkin pathway regulates mitochondrial dynamics and function in mammalian hippocampal and dopaminergic neurons. Hum. Mol. Genet. 20, 3227–3240 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Narendra, D., Tanaka, A., Suen, D. F. & Youle, R. J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183, 795–803 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Narendra, D., Kane, L. A., Hauser, D. N., Fearnley, I. M. & Youle, R. J. p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy 6, 1090–1106 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Narendra, D. et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 8, e1000298 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Geisler, S. et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nature Cell Biol. 12, 119–131 (2010).
  Article CAS PubMed Google Scholar
• Lee, J. Y., Nagano, Y., Taylor, J. P., Lim, K. L. & Yao, T. P. Disease-causing mutations in Parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy. J. Cell Biol. 189, 671–679 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Matsuda, N. et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J. Cell Biol. 189, 211–221 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Vives-Bauza, C. et al. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc. Natl Acad. Sci. USA 107, 378–383 (2010).
  Article CAS PubMed Google Scholar
• Chan, N. C. et al. Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum. Mol. Genet. 20, 1726–1737 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Yoshii, S. R., Kishi, C., Ishihara, N. & Mizushima, N. Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane. J. Biol. Chem. 286, 19630–19640 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, X. et al. PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 147, 893–906 (2011). This study demonstrated that the PINK1–parkin pathway also regulates mitochondrial transport, which may help to quarantine parkin-labelled damaged mitochondria for clearance by mitophagy.
  Article CAS PubMed PubMed Central Google Scholar
• Deng, H., Dodson, M. W., Huang, H. & Guo, M. The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila. Proc. Natl Acad. Sci. USA 105, 14503–14508 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Yang, Y. et al. Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery. Proc. Natl Acad. Sci. USA 105, 7070–7075 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Poole, A. C. et al. The PINK1/Parkin pathway regulates mitochondrial morphology. Proc. Natl Acad. Sci. USA 105, 1638–1643 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Park, J., Lee, G. & Chung, J. The PINK1–Parkin pathway is involved in the regulation of mitochondrial remodeling process. Biochem. Biophys. Res. Commun. 378, 518–523 (2009).
  Article CAS PubMed Google Scholar
• Mortiboys, H. et al. Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Ann. Neurol. 64, 555–565 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Exner, N. et al. Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin. J. Neurosci. 27, 12413–12418 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Wood-Kaczmar, A. et al. PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons. PLoS ONE 3, e2455 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Dagda, R. K. et al. Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J. Biol. Chem. 284, 13843–13855 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Sandebring, A. et al. Mitochondrial alterations in PINK1 deficient cells are influenced by calcineurin-dependent dephosphorylation of dynamin-related protein 1. PLoS ONE 4, e5701 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Lutz, A. K. et al. Loss of parkin or PINK1 function increases Drp1-dependent mitochondrial fragmentation. J. Biol. Chem. 284, 22938–22951 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Ziviani, E., Tao, R. N. & Whitworth, A. J. Drosphila Parkin requires PINK1 for mitochondrial translocation and ubiquitinates Mitofusin. Proc. Natl Acad. Sci. USA 107, 5018–5023 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Gegg, M. E. et al. Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum. Mol. Genet. 19, 4861–4870 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Poole, A. C. et al. The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/parkin pathway. PLoS ONE 5, e10054 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Tanaka, A. et al. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J. Cell Biol. 191, 1367–1380 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Miller, K. E. & Sheetz, M. P. Axonal mitochondrial transport and potential are correlated. J. Cell Sci. 117, 2791–2804 (2004). This study demonstrates that mitochondria with a high membrane potential are transported anterogradely towards distal processes, whereas damaged mitochondria return to the cell body following acute depolarization.
  Article CAS PubMed Google Scholar
• Katsumata, K. et al. Dynein- and activity-dependent retrograde transport of autophagosomes in neuronal axons. Autophagy 6, 378–385 (2010).
  Article CAS PubMed Google Scholar
• Cai, Q. & Sheng, Z. H. Uncovering the role of Snapin in regulating autophagy-lysosomal function. Autophagy 7, 445–447 (2011).
  Article PubMed PubMed Central Google Scholar
• Lee, S., Sato, Y. & Nixon, R. A. Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer's-like axonal dystrophy. J. Neurosci. 31, 7817–7830 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Verburg, J. & Hollenbeck, P. J. Mitochondrial membrane potential in axons increases with local nerve growth factor or semaphorin signaling. J. Neurosci. 28, 8306–8315 (2008). This paper provides evidence that mobile and stationary mitochondria show no difference in membrane potential under physiological conditions.
  Article CAS PubMed PubMed Central Google Scholar
• Green, D. R. & Houten, B. V. SnapShot: mitochondrial quality control. Cell 147, 950–950e1 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Karki, S. & Holzbaur, E. L. Cytoplasmic dynein and dynactin in cell division and intracellular transport. Curr. Opin. Cell Biol. 11, 45–53 (1999).
  Article CAS PubMed Google Scholar
• Foth, B. J., Goedecke, M. C. & Soldati, D. New insights into myosin evolution and classification. Proc. Natl Acad. Sci. USA 103, 3681–3686 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Cai, Q. & Sheng, Z.-H. in Mitochondrial Dynamics and Neurodegeneration (ed. Lu, B.) 139–168 (Springer, Dordrecht, 2011).
  Book Google Scholar
• de Castro, I. P., Martins, L. M. & Tufi, R. Mitochondrial quality control and neurological disease: an emerging connection. Expert Rev. Mol. Med. 19, e12 (2010).
  Article CAS Google Scholar
• Tatsuta, T. & Langer, T. Quality control of mitochondria: protection against neurodegeneration and ageing. EMBO J. 27, 306–314 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Detmer, S. A. & Chan, D. C. Functions and dysfunctions of mitochondrial dynamics. Nature Rev. Mol. Cell Biol. 8, 870–879 (2007).
  Article CAS Google Scholar
• Westermann, B. Mitochondrial fusion and fission in cell life and death. Nature Rev. Mol. Cell Biol. 11, 872–884 (2010).
  Article CAS Google Scholar
• Youle, R. J. & Narendra, D. P. Mechanisms of mitophagy. Nature Rev. Mol. Cell Biol. 12, 9–14 (2011).
  Article CAS Google Scholar
• Wang, X. et al. The role of abnormal mitochondrial dynamics in the pathogenesis of Alzheimer's disease. J. Neurochem. 109, 153–159 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Rui, Y., Tiwari, P., Xie, Z. & Zheng, J. Q. Acute impairment of mitochondrial trafficking by β-amyloid peptides in hippocampal neurons. J. Neurosci. 26, 10480–10487 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Stokin, G. B. et al. Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science 307, 1282–1288 (2005).
  Article CAS PubMed Google Scholar
• Sasaki, S. & Iwata, M. Impairment of fast axonal transport in the proximal axons of anterior horn neurons in amyotrophic lateral sclerosis. Neurology 47, 535–540 (1996).
  Article CAS PubMed Google Scholar
• De Vos, K. J. et al. Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content. Hum. Mol. Genet. 16, 2720–2728 (2007).
  Article CAS PubMed Google Scholar
• Magrané, J. et al. Mutant SOD1 in neuronal mitochondria causes toxicity and mitochondrial dynamics abnormalities. Hum. Mol. Genet. 18, 4552–4564 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Shi, P., Ström, A. L., Gal, J. & Zhu, H. Effects of ALS-related SOD1 mutants on dynein- and KIF5-mediated retrograde and anterograde axonal transport. Biochim. Biophys. Acta 1802, 707–716 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Millecamps, S. et al. Alsin is partially associated with centrosome in human cells. Biochim. Biophys. Acta 1745, 84–100 (2005).
  Article CAS PubMed Google Scholar
• Shan, X., Chiang, P. M., Price, D. L. & Wong, P. C. Altered distributions of Gemini of coiled bodies and mitochondria in motor neurons of TDP-43 transgenic mice. Proc. Natl Acad. Sci. USA 107, 16325–16330 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Bosco, D. A. et al. Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nature Neurosci. 13, 1396–1403 (2010).
  Article CAS PubMed Google Scholar
• Zhu, Y. B. & Sheng, Z. H. Increased axonal mitochondrial mobility does not slow amyotrophic lateral sclerosis (ALS)-like disease in mutant SOD1 mice. J. Biol. Chem. 286, 23432–23440 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Caviston, J. P. & Holzbaur, E. L. Huntingtin as an essential integrator of intracellular vesicular trafficking. Trends Cell Biol. 19, 147–155 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Caviston, J. P. et al. Huntingtin facilitates dynein/dynactin-mediated vesicle transport. Proc. Natl Acad. Sci. USA 104, 10045–10050 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Colin, E. et al. Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons. EMBO J. 27, 2124–2134 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Trushina, E. et al. Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol. Cell. Biol. 24, 8195–8209 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Chang, D. T., Rintoul, G. L., Pandipati, S. & Reynolds, I. J. Mutant huntingtin aggregates impair mitochondrial movement and trafficking in cortical neurons. Neurobiol. Dis. 22, 388–400 (2006).
  Article CAS PubMed Google Scholar
• Song, W. et al. Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nature Med. 17, 377–382 (2011).
  Article CAS PubMed Google Scholar
• Orr, A. L. et al. N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking. J. Neurosci. 28, 2783–2792 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, H. J., Khoshaghideh, F., Lee, S. & Lee, S. J. Impairment of microtubule-dependent trafficking by overexpression of α-synuclein. Eur . J. Neurosci. 24, 3153–3162 (2006).
  Article PubMed Google Scholar
• Yang, F. et al. Parkin stabilizes microtubules through strong binding mediated by three independent domains. J. Biol. Chem. 280, 17154–17162 (2005).
  Article CAS PubMed Google Scholar
• Gillardon, F. Leucine-rich repeat kinase 2 phosphorylates brain tubulin-beta isoforms and modulates microtubule stability — a point of convergence in Parkinsonian neurodegeneration? J. Neurochem. 110, 1514–1522 (2009).
  Article CAS PubMed Google Scholar