People with amyotrophic lateral sclerosis struggle to move, and it appears some of their organelles have the same problem. Mitochondria normally sashay up and down neuronal axons, arriving fresh at the synapse and smartly returning to the cell body to be recycled. But in ALS, these organelles flounder in their travels as well as in their ability to provide the energy that neurons crave, according to new research. In the January 4 Journal of Neuroscience, researchers from the Weill Medical College of Cornell University in New York City report that in a neuron model for ALS, mitochondria exhibit a variety of defects, including lackadaisical fusion and a lollygagging passage from axon tips to the cell body.

Mitochondrial defects are associated with Alzheimer’s, Parkinson’s (see ARF related news story), and Huntington’s diseases (see ARF related news story). “This study adds ALS as one of the neurodegenerative diseases where mitochondrial dynamics is clearly affected and most likely playing a role in neurodegeneration,” said study senior author Giovanni Manfredi, who led the work with first author Jordi Magrané. Their and others’ work previously indicated a role for mitochondria (reviewed in Magrané and Manfredi, 2009) and axonal transport (De Vos et al., 2007; see ARF related news story and ARF news story) in degeneration of motor neurons in ALS, but “this is clearly the best and most comprehensive study on this topic as yet,” commented Flint Beal, who is also at Weill Medical College but was not involved in the publication.

To label mitochondria and follow their comings and goings, Magrané hooked the mitochondrial-targeting pre-sequence from cytochrome c oxidase to a photo-switchable fluorescent protein called Dendra. Dendra starts out green, but when photoactivated by blue-green light converts irreversibly to red. Magrané transfected this mitoDendra into primary embryonic motor neurons. The cells came from rats expressing human SOD1 with the G93A mutation that causes an inherited form of ALS. As controls, Magrané used rats expressing wild-type human SOD1 as well as non-transgenic animals.

To examine mitochondrial fusion, the researchers photo-converted some of the mitoDendra in each cell soma to red. Then, as green- and red-labeled mitochondria mixed, yellow mitochondria appeared, signifying fusion of organelles. In motor neurons from non-transgenic rats, it took approximately 40 minutes for yellow signals to appear. This process took more than twice as long in mSOD1 cells. Similarly, in the axons of the mSOD1 neurons, the scientists observed that mitochondria—specifically those moving in the retrograde direction—fused with each other approximately half as often as they did in control axons.

The researchers then examined mitochondrial transport along axons. In control neurons, the organelles traveled in the anterograde direction at approximately 0.2 microns per second and retrogradely at about 0.3 microns per second. While anterograde transport proceeded at normal velocity in mSOD1 cells, mitochondria coming back up in the retrograde direction traveled more slowly and paused more often than in control axons. They averaged only 0.2 microns per second. Since retrograde-moving mitochondria are destined to be recycled into fresh new organelles in the cell body, this leisurely pace could impact the production of reinvigorated mitochondria, Manfredi suggested.

Altered transport and fusion could alter the size of mitochondria, so Magrané measured the length of the organelles in axons as the cells aged. Mitochondria were shorter in the mSOD1 neurons, and the defect appeared to start at the axon tips and work toward the cell body. At five days in culture, control cells possessed mitochondria of approximately three microns in length in both proximal and distal areas. In the mSOD1 axons, the proximal mitochondria remained normal size, but the distal ones were only two microns long. After 10 days in culture, proximal mitochondria stretched to four microns in non-transgenic neurons, but only 3.3 microns in mSOD1 neuronal cultures.

This distal-first sequence of events in culture mirrors the progression of ALS pathology, in which atrophy appears to begin at the neuromuscular junction and progress to the cell body in a “dying back” of the axon (Fischer et al., 2004), noted Xiongwei Zhu and Xinglong Wang, of Case Western Reserve University in Cleveland, Ohio, in an e-mail to ARF. The data “support a critical role of mitochondria dysfunction in the dying back mechanism of the SOD1-familial ALS model,” wrote Zhu and Wang, who were not involved in the current study.

Manfredi and Magrané wondered if all retrograde transport would be affected, or only that of mitochondria. To find out, they used Dendra to label membrane-bound organelles (MBOs), vesicles that also shuttle up and down axons. MBO transit was unaffected by mSOD1, suggesting the axon’s rails and engines must be intact. Mitochondrial-trafficking deficiency also only appeared in motor neurons, Magrané found. When he examined mitochondrial dynamics in primary cortical neurons, transport was normal in the mSOD1-expressing cells.

The researchers do not yet know how mSOD1 alters mitochondrial transport. It might interrupt the organelles’ interactions with microtubules or molecular motors, Manfredi speculated (Ström et al., 2008). While mSOD1 is found all over the cell, he and Magrané have previously shown that when the mutant protein is targeted solely to mitochondria, it recapitulates many features of ALS (see ARF related news story on Igoudjil et al., 2011; Magrané et al., 2009). Therefore, it is possible that some intrinsic deficiency in mSOD1-toting mitochondria affects their morphology and transport.

“I think this work will solidify the concept that impairment of mitochondrial dynamics in axons can be a significant contributing factor to ALS etiology,” said Haining Zhu of the University of Kentucky in Lexington, who was not involved in the study. And mutant SOD1 is likely not the only way to muck up mitochondrial transport. Other rodent models for ALS, based on mutations in genes such as TDP-43, also exhibit abnormal mitochondrial morphology (see ARF related news story on Xu et al., 2010). Those genetic mutations, however, account for only a small percentage of human ALS. Most cases are sporadic, and mitochondrial transport might turn out to be amiss in those motor neurons, too, Beal suggested. “I think it is feasible that it is going to be a generalized problem,” he said.

Moreover, mitochondrial defects are emerging as a common thread among neurodegenerative disease. “Neurons are energy-demanding,” Haining Zhu noted, suggesting, “you may have different insults in different diseases, but they all could lead to mitochondrial abnormality.”—Amber Dance


  1. This is a very well-executed study with very careful and detailed measurement of mitochondrial morphology and transport in motor neurons in an ALS model, and which extends the authors’ previous findings (Magrané et al., 2009). Mitochondrial Dendra is a very useful tool, but this is not the novelty here, since the same mitoDendra is already widely used by many groups. In this study, the authors convincingly demonstrated that mutant SOD1 impaired mitochondrial fusion and retrograde transport of mitochondria only in motor neurons. Of more pathogenic significance is that they found mitochondrial fragmentation progresses from distal to proximal segments over time (at five days in vitro, only distal segments demonstrated fragmented mitochondria, while at DIV10, both distal and proximal mitochondria fragment). That anterograde-moving mitochondria in mutant SOD1 motor neurons have lower mitochondrial membrane potential than those in controls supports a critical role of mitochondria dysfunction in the dying back mechanism of the SOD1-FALS model. They also confirmed the correlation between lack of mitochondrial support and synaptic abnormalities (Wang et al., 2009).

    Overall, this study convincingly demonstrated that mutant SOD1 affects mitochondrial dynamics, adding ALS to the expanding list of neurodegenerative diseases involving abnormal mitochondrial dynamics, such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease (Wang et al., 2008; Wang et al., 2008; Wang et al., 2009; Shirendeb et al., 2012; 2011; Manczak et al., 2011; Calkins et al., 2011; Song et al., 2011; Imai and Lu, 2011). These studies suggest that abnormal mitochondrial dynamics may be a common downstream pathway mediating or amplifying mitochondrial and neuronal dysfunction during the course of neurodegeneration. It is, therefore, of interest to determine how mutant SOD1 affects mitochondrial dynamics. (Is fission affected? Is it necessary for mutant SOD1 to interact with mitochondria? How does mutant SOD1 interact with the fission/fusion machinery?) It will also be interesting to know if SOD1 shares similar mechanisms with other pathogenic proteins.


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News Citations

  1. Abnormal Mitochondrial Dynamics—Early Event in AD, PD?
  2. Mutant Huntingtin Linked to Mitochondrial Dysfunction
  3. Chicago: Axonal Transport Not So Fast in Neurodegenerative Disease
  4. Research Brief: SOD1 in Sporadic ALS Suggests Common Pathway
  5. Mutant Meddling in Mitochondria Partly Mimics ALS Pathology
  6. Paper Alert: Malformed Mitochondria in the Latest TDP-43 Mouse

Paper Citations

  1. . Mitochondrial function, morphology, and axonal transport in amyotrophic lateral sclerosis. Antioxid Redox Signal. 2009 Jul;11(7):1615-26. PubMed.
  2. . Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content. Hum Mol Genet. 2007 Nov 15;16(22):2720-8. Epub 2007 Aug 28 PubMed.
  3. . Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol. 2004 Feb;185(2):232-40. PubMed.
  4. . Interaction of amyotrophic lateral sclerosis (ALS)-related mutant copper-zinc superoxide dismutase with the dynein-dynactin complex contributes to inclusion formation. J Biol Chem. 2008 Aug 15;283(33):22795-805. PubMed.
  5. . In vivo pathogenic role of mutant SOD1 localized in the mitochondrial intermembrane space. J Neurosci. 2011 Nov 2;31(44):15826-37. PubMed.
  6. . Mutant SOD1 in neuronal mitochondria causes toxicity and mitochondrial dynamics abnormalities. Hum Mol Genet. 2009 Dec 1;18(23):4552-64. PubMed.
  7. . Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice. J Neurosci. 2010 Aug 11;30(32):10851-9. PubMed.

Further Reading


  1. . SOD1 targeted to the mitochondrial intermembrane space prevents motor neuropathy in the Sod1 knockout mouse. Brain. 2011 Jan;134(Pt 1):196-209. PubMed.
  2. . Retrograde axonal transport: pathways to cell death?. Trends Neurosci. 2010 Jul;33(7):335-44. PubMed.
  3. . Mitochondrial dysfunction is a converging point of multiple pathological pathways in amyotrophic lateral sclerosis. J Alzheimers Dis. 2010;20 Suppl 2:S311-24. PubMed.
  4. . A switch in retrograde signaling from survival to stress in rapid-onset neurodegeneration. J Neurosci. 2009 Aug 5;29(31):9903-17. PubMed.

Primary Papers

  1. . Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons. J Neurosci. 2012 Jan 4;32(1):229-42. PubMed.