Tau is toxic to neurons, but exactly how is not crystal clear. A new study in the August 23 Neuron suggests that tau overexpression indirectly elongates mitochondria, which then malfunction and cause cell death. Mel Feany, Harvard Medical School, and colleagues found that in fruit flies, tau binds and stabilizes the cytoskeletal protein F-actin, preventing a key mitochondrial fission protein from reaching the organelles. The mechanism could be one of several that sabotage mitochondria, leading to cell death. "Overall, it is very compelling evidence demonstrating that tau overexpression causes mitochondrial elongation in Drosophila," said Xiongwei Zhu, Case Western Reserve University, Cleveland, Ohio, who was not involved in the study.

A delicate balance of mergers and divisions, known respectively as fusion and fission, maintain mitochondria at just the right length. If that balance goes out of whack, there can be serious consequences for cell health. Abnormal mitochondria have been implicated in several neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases (see ARF related news story) as well as Huntington's disease (see ARF related news story) and ALS (see ARF related news story).

Mitochondria move about the cell via tethers to cytoskeletal actin and microtubule filaments. Feany's lab previously found that phosphorylated tau binds to and stabilizes filamentous (F) actin in both human tau-expressing flies and mice (see ARF related news story on Fulga et al., 2007). This led to bundled, rod-like actin and neurodegeneration, but it was unclear how the neurons died.

To probe that question, first author Brian DuBoff expressed human tau with an FTDP-17-linked missense mutation (R406W) in fruit flies. Using laser-scanning confocal microscopy, he saw neuronal mitochondria that were more than twice as long in transgenic flies as controls, suggesting an abnormally low amount of fission. Cell death followed shortly thereafter. Mitochondria also appeared to be elongated in rTg4510 and K3 mouse neurons expressing human tau with P301L or K369I mutations, respectively. Compared to controls, brains from animals expressing tau produced more superoxide. This result implied that the longer mitochondria promoted oxidative stress, leading to cell death.

What extended the mitochondria? To divide, the organelles use a fission-driving dynamin-related GTPase called DRP1, which keeps mitochondria small. In control, but not in tau transgenic flies, DRP1 latched onto the organelles, but it appeared that F-actin stabilization prevented DRP1 from reaching the mitochondria in tau transgenics. To confirm that F-actin bundles were responsible, DuBoff used two pro-bundling proteins, WASP and forked, to stabilize actin. Like human tau, these proteins caused mitochondria to stretch, and the organelles lacked DRP1. The GTPase instead accumulated on F-actin. The findings suggest that DRP1 accumulates more on the stabilized form of F-actin, and then fails to reach the mitochondria.

What mediates the DRP1 and mitochondria interaction? Myosins, which are motor proteins, are known to tether both proteins and organelles to actin, or even move them along actin strands. To find out if myosins were involved, the group looked at eight myosin fly knockouts currently available to find out if one type led to the distended mitochondria. Only mutations in fly homologues of mammalian myosin II heavy and light chains promoted long mitochondria that seemed short on DRP1. Fewer mitochondria co-precipitated with F-actin in myosin II knockouts, suggesting that the myosin homologues attach the organelles to F-actin, where they can then bind DRP1.

"One idea we favor is that with increased F-actin, either the mitochondria or the DRP1 cannot be appropriately transported, and thus DRP1 cannot translocate to mitochondria," said Feany. But there are other possibilities, she said, including an atypical F-actin orientation that impairs interactions. "The exact mechanism remains the subject of future study," she added.

The result could extend recent findings from Lennart Mucke and colleagues at the Gladstone Institute of Neurological Disease in San Francisco, California, who found that an absence of tau prevents Aβ's toxic dampening of mitochondrial transport (see ARF related news story on Vossel et al., 2010), said ShiDu Yan, University of Kansas, Lawrence. Based on the current report, a deficit in mitochondrial morphology could also be blocked by depletion of tau.

Could the same process be going on in humans? "The fact that we replicated many of the Drosophila findings in mouse tauopathy models suggests it could be going on in mammals," Feany said. In addition, Zhu and colleagues observed DRP1 suppression and elongated mitochondria in fibroblasts from AD patients (see Wang et al., 2008), suggesting a similar chain of events may unfold in people with Alzheimer’s. But it is impossible to know until the model is tested in humans, Feany said. "This paper helps us to understand the DRP1-actin link and a basic mechanism, but relevance to disease states such as Alzheimer's is unclear," said Hemachandra Reddy, Oregon Science and Health University, Beaverton.

There are other hints that DRP1 may be awry in AD. Reddy found recently that phosphorylated tau might bind directly to DRP1 and cause mitochondrial fragmentation (see Manczak and Reddy, 2012). Aβ may exert its own effect on DRP1 as well, by driving nitric oxide production, which drives DRP1-induced fission and mitochondrial fragmentation (see ARF related news story). It still is not clear whether mitochondria are fragmented or elongated in human disease, or how Aβ pathology influences mitochondrial length. "We need more research in that direction," said Reddy.—Gwyneth Dickey Zakaib.

DuBoff B, Götz J, Feany MB. Tau Promotes Neurodegeneration via DRP1 Mislocalization In Vivo. Neuron 2012 Aug 23; 75, 618-632. Abstract


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Comments on News and Primary Papers

  1. A Critical Role of Mitochondrial Dynamics in the Pathogenesis of AD
    Dr. Feany and colleagues should be congratulated for an elegant Drosophila genetic study. They convincingly demonstrated that tau overexpression causes mitochondrial elongation in Drosophila through actin-stabilization mediated DLP1 (aka Drp1) mislocalization. Because mitochondrial fission/fusion deficiency may lead to mitochondria with heterogeneous size, it can be very tricky, or sometimes misleading, to determine whether mitochondrial fission/fusion is impaired in vivo based on measurement of mitochondrial length at a static point only. Ideally, the conclusion should be strengthened by genetic manipulation of mitochondrial dynamics. Drosophila is a very useful tool in this respect. Indeed, on top of the finding that mitochondria become elongated in tau overexpressing Drosophila, DuBoff et al. further demonstrated that Mfn knockdown or DLP1 overexpression rescued tau-induced mitochondrial elongation and toxic effects, which makes the conclusion more convincing.

    Their further genetic manipulations demonstrated that actin stabilization impairs mitochondrial translocation of DLP1, which results in elongation. However, this observation appears contradictory to a prior finding that reported disruption of actin filaments attenuated fission and recruitment of DRP1 to mitochondria (De Vos et al., 2005). The authors proposed a model to try to reconcile the difference: “DRP1 and mitochondria are recruited to F-actin, followed by actin-based translocation, leading to mitochondrial localization of DRP1 and subsequent mitochondrial fission”. Basically this is a two-step model: F-actin recruitment of DLP1 and mitochondria as step one, and actin-based DLP1 translocation to mitochondria as step two. There are questions remaining to be answered regarding both steps. Does tau overexpression increase F-actin-associated DLP1, for example? And does reversing tau-induced actin stabilization also reduce F-actin associated DLP1? As for step two, what is the evidence to support the actin-based DLP1 translocation to mitochondria? And how and why is actin involved in DLP1 translocation?

    There are other unanswered questions as well. Abnormal mitochondrial distribution is observed in AD and AD models (Wang et al., 2008a; Wang et al., 2008b; Wang et al., 2009), what about this fly model? And since tau is a microtubule binding protein, are microtubules or tubulin involved and how can that be answered? Reddy et al. demonstrated an interaction between tau and DLP1 (Manczak and Reddy, 2012), how does that fit into the model?

    The next big question is whether these observations in Drosophila have parallels in mammals. The authors tried to demonstrate that mitochondrial elongation occurs in the brain of Tau transgenic mice by measuring mitochondrial length under the light microscope after immunostaining brain sections with a mitochondrial marker. This is not optimal since individual mitochondrion can hardly be distinguished using light microscopy. Ideally, electron microscopy analysis of mitochondrial ultrastructure and genetic manipulation of mitochondrial dynamics in tau mice will give a more definite answer. Given the ongoing debate over the different effect of PINK1 mutations on mitochondrial morphology in Drosophila study (i.e., PINK1 mutations cause mitochondrial elongation in Drosophila) and mammalian cell study (i.e., PINK1 mutations cause mitochondrial fragmentation in mammalian cells), we should be very cautious when extending any findings in Drosophila to mammalian systems. Another issue that needs to be considered in relation to human tauopathies is that overexpression of caspase cleaved tau or tau hyperphosphorylation (i.e., cardinal features of tauopathies) causes mitochondrial fragmentation in mammalian cells. Therefore, how mitochondria may be affected in tau transgenic mice needs to be more carefully determined.

    Overall, it is clear that mitochondrial dynamics is impaired in AD brain and APP transgenic mouse models (Hirai et al., 2001; Wang et al., 2009; Cho et al., 2009; Du et al., 2010; Calkins et al., 2011; Manczak et al., 2011; Manczak and Reddy, 2012). In vitro studies from multiple groups convincingly demonstrated that APP overexpression or exposure to Abeta causes excessive mitochondrial fission and abnormal mitochondrial distribution, which contributes to mitochondrial dysfunction and synaptic deficits (Barsoum et al., 2006; Wang et al., 2008a; Wang et al., 2008b; Cho et al., 2009; Wang et al., 2009; Du et al., 2010; Calkins et al., 2011; Manczak et al., 2011; Manczak and Reddy, 2012). Mel Feany’s study further demonstrated that abnormal mitochondrial dynamics also mediates tau toxicity, which further strengthens the critical role of mitochondrial dynamics in the pathogenesis of AD.

    View all comments by Xiongwei Zhu


News Citations

  1. Abnormal Mitochondrial Dynamics—Early Event in AD, PD?
  2. Mutant Huntingtin Linked to Mitochondrial Dysfunction
  3. Mitochondria Stumble Their Way Along Axons in ALS Model
  4. New Takes on Tau: Does It Stabilize Actin, Flag Neurogenesis?
  5. The Plot Thickens: The Complicated Relationship of Tau and Aβ
  6. NO Kidding? Mitochondria Fission Protein Linked to Neurodegeneration

Paper Citations

  1. . Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nat Cell Biol. 2007 Feb;9(2):139-48. PubMed.
  2. . Tau reduction prevents Abeta-induced defects in axonal transport. Science. 2010 Oct 8;330(6001):198. PubMed.
  3. . Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer's disease patients. Am J Pathol. 2008 Aug;173(2):470-82. PubMed.
  4. . Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: implications for mitochondrial dysfunction and neuronal damage. Hum Mol Genet. 2012 Jun 1;21(11):2538-47. PubMed.
  5. . Tau promotes neurodegeneration via DRP1 mislocalization in vivo. Neuron. 2012 Aug 23;75(4):618-32. PubMed.

Further Reading

Primary Papers

  1. . Tau promotes neurodegeneration via DRP1 mislocalization in vivo. Neuron. 2012 Aug 23;75(4):618-32. PubMed.