You can’t keep a good mitochondrion down. Or maybe you can. In today’s Cell, researchers led by Zu-Hang Sheng at the National Institute for Neurological Disorders and Stroke report that the protein syntaphilin docks mitochondria to microtubules, impeding their transport and preventing their delivery to synapses. Genetically ablating syntaphilin boosts the mobility of mitochondria and enhances short-term facilitation, suggesting that syntaphilin may play a role in regulating neural activity, the scientists report. The finding may help researchers understand the relationship between defective mitochondrial transport and neurological and neurodegenerative disorders.

Being energy hogs, neurons are packed with mitochondria, particularly their synapses. Sheng and colleagues previously showed that syntaphilin can suppress presynaptic function (see Lao et al., 2000), which prompted them to go after the function of the protein. Using immunohistochemistry, first author Jian-Sheng Kang and colleagues found that syntaphilin (SNPH) occurs mostly in axons. Furthermore, using cultured hippocampal neurons, they found that the majority of SNPH co-localized with axonal mitochondria, and that deleting an axon-sorting domain redistributed SNPH into mitochondria in various other cellular locales, including the soma and dendrites. The finding suggests a specific relationship between wild-type syntaphilin and axonal mitochondria.

To test if that relationship might affect mitochondrial transport, Kang and colleagues observed the organelles with time-lapse confocal microscopy. They labeled mitochondria with red fluorescent protein (DsRed) and syntaphilin with green fluorescent protein (GFP). The researchers found that while 38 percent of axonal mitochondria are normally on the move, mitochondria bound to GFP-SNPH were stationary. It appears that SNPH binding to mitochondria locks them to microtubules, since SNPH lacking its microtubule binding domain did not impede mitochondrial motion. In fact, by simply tacking syntaphilin’s microtubule binding domain to the mitochondrial outer membrane protein TOM22, the researchers were able to block transport of the organelles. Interestingly, the syntaphilin microtubule binding domain is unlike any other known microtubule binding protein, suggesting that “SNPH likely acts as a docking receptor specific for axonal mitochondria through a unique interaction with the microtubule-based cytoskeleton,” write the authors.

Why does the SNPH-mitochondrial interaction matter? To address this, the authors made SNPH knockout mice. Both homo- and heterozygous strains were viable and fertile. Though their overall appearance was similar to wild-type mice, they did have subtle impairments in motor ability. For example, while the SNPH nulls balanced fine on the rotorod at constant speed, they faltered sooner than wild-type mice when the rod accelerated. As for axonal mitochondria, substantially more (76 percent) of them were on the move in hippocampal neurons cultured from SNPH knockouts than in neurons from wild-type mice (36 percent).

What might happen to the neuron when its mitochondria move more? For one, the density of axonal mitochondria drops (~ 1 per 10 μm in SNPH KOs versus 1.7 in wild-type); for another, the ratio of anterograde to retrograde mitochondrial movement changes from 1.27 to 1.03. These two changes “suggest that the SNPH-mediated docking/retention contributes to the maintenance of proper mitochondrial density in axons,” write the authors. Synapses also appear to be affected. The proportion of presynaptic boutons with proximal mitochondria within 0.5 μm goes down from 57 percent to 33 percent in SNPH knockouts, though the density of boutons stays normal. Given the primary role of mitochondria as energy providers, their failure to dock in and around synapses could deprive some of much needed ATP. The authors suggest this might be particularly significant for neurons with long axonal processes such as motor neurons.

Could the redistribution of mitochondria in SNPH null animals affect synaptic transmission? To test this, the authors measured excitatory post-synaptic currents (EPSC) in cultured hippocampal neurons. They found that while basal activity was normal in SNPH-negative neurons, a train of high-frequency pulses induced enhanced currents that indicate short-term facilitation. “One possible explanation for this observation is a rapid buildup of intracellular [Ca2+] in presynaptic terminals during intensive stimulation,” suggest the authors. In support of this, they demonstrated increased Ca2+ using fluorescent imaging and were able to abolish the enhanced short-term facilitation phenotype using the calcium chelator EGTA-AM. This would be in keeping with a proposed role for mitochondria in calcium homeostasis: mitochondria help balance calcium at some synapses by mopping up Ca2+ released by tetanic stimulation (see Jonas et al., 2006).

Though Sheng and colleagues previously reported that syntaphilin is involved in synaptic endocytosis (see Das et al., 2003), these findings also support a role of syntaphilin in docking mitochondria to microtubules and regulating their motility. “Such a mechanism may enable neurons to maintain proper densities of stationary mitochondria within axons and in the proximity of synapses," write the authors. Given that defective mitochondrial transport has been implicated in Charcot-Marie-Tooth Disease (see Baloh et al., 2007), Huntington disease (see Trushina et al., 2004), and potentially other neurodegenerative disorders (see for review Stokin and Goldstein, 2006), the findings may help researchers more fully understand the role of mitochondrial transport in neurons and neurologic disorders.—Tom Fagan


  1. We know, based on Mandelkow’s and Hirokawa’s work, that accumulation of tau in neurons inhibits axonal transport, and may affect synaptic function. Hyperphosphorylation of tau detaches tau from microtubules, and restores axonal transport. However, subsequent formation of neurofibrillary tangles (NFTs) may also affect synaptic function, leading to neuronal dysfunction in disease. Therefore, tau is thought to have a dual role in synapse dysfunction. Sheng’s paper makes us reconsider the mode of mitochondrial axonal transport. Depletion of syntaphilin liberated mitochondria to a mobile state, and affected short-term facilitation in synapses, which means that detaching tau from microtubules by phosphorylation may affect synapse function by altering the mobile state of mitochondria. Indeed, in our recent manuscript, when tau was hyperphosphorylated with age in mice expressing human tau, the animals showed an impairment of spatial memory accompanied by synapse loss in the entorhinal cortex. If the state of tau alters the interplay between mitochondria and syntaphilin, the mobile state of mitochondria may be a cause of memory impairment in these aged mice.

  2. The present paper makes an important contribution to understanding the proteins which are responsible for docking of axonal mitochondria and for controlling their mobility. The authors have identified a role for axon-targeted syntaphilin in mitochondrial docking through its interaction with microtubules. When they overexpressed syntaphilin, they report that axonal mitochondria lose mobility. They carried out elegant experiments in which they deleted the mouse syntaphilin gene. This resulted in a higher proportion of axonal mitochondria in the mobile state and reduced the density of mitochondria in axons. Electrophysiologically, the mutant neurons exhibited enhanced short-term facilitation during prolonged stimulation. This appears to be due to an effect on calcium signaling at the presynaptic boutons. They were able to rescue the phenotype by reintroducing the syntaphilin gene into the mutant neurons.

    These are important findings in an area that is receiving increasing attention. It is likely that mitochondrial mobility and distribution may be important in neurodegenerative diseases. Impaired axonal transport of mitochondria has been identified in almost all major neurodegenerative diseases including Huntington disease (HD), Alzheimer disease (AD) and amyotrophic lateral sclerosis (ALS). In addition, almost all neurodegenerative diseases tend to have degeneration of the distal synapses. This is true in all the major diseases such as AD, Parkinson disease, HD, and ALS. This may be a consequence of impaired axonal transport. The ability to test this by utilizing the knockout mice could prove to be extremely valuable. There are two major possibilities. Increasing axonal transport of mitochondria could be beneficial, since it may allow damaged mitochondria to return to the nucleus where they may be repaired or autophagocytosed. On the other hand, it might lead to fewer mitochondria in the distal synapse, which could further impair distal synaptic function. These will be interesting areas for further investigation.

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Paper Citations

  1. . Syntaphilin: a syntaxin-1 clamp that controls SNARE assembly. Neuron. 2000 Jan;25(1):191-201. PubMed.
  2. . BCL-xL regulates synaptic plasticity. Mol Interv. 2006 Aug;6(4):208-22. PubMed.
  3. . Syntaphilin binds to dynamin-1 and inhibits dynamin-dependent endocytosis. J Biol Chem. 2003 Oct 17;278(42):41221-6. PubMed.
  4. . Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. J Neurosci. 2007 Jan 10;27(2):422-30. PubMed.
  5. . Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol Cell Biol. 2004 Sep;24(18):8195-209. PubMed.
  6. . Axonal Transport and Alzheimer's Disease. Annu Rev Biochem. 2006 Mar 16; PubMed.

Further Reading

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Primary Papers

  1. . Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation. Cell. 2008 Jan 11;132(1):137-48. PubMed.