Energy drain. Mitochondria can swell up and ultimately rupture in people with ALS depleting energy reserves in motor neurons. Image: NIA, NIH.

With Biogen Idec’s dexpramipexole now in phase III clinical trials and the phase III results soon to be in for Trophos’ olesoxime, treatment strategies which keep degenerating motor neurons alive by targeting mitochondria are gathering steam. But researchers remain unsure whether or not these drugs target these intracellular power plants or even whether a power outage causes the disease.

Now, researchers from Weill Cornell Medical College put this theory to the test by generating mice that exclusively produce ALS-associated mutant superoxide dismutase 1 (mSOD1) in mitochondria and look for tell tale signs of the disease.  The researchers find that these mice develop muscle weakness and motor impairment but do not develop paralysis or die of respiratory failure.

“We observe a progressive decline in mitochondrial function,” says Giovanni Manfredi PhD, “but the disease is not as severe and not as lethal.”

These results suggest that a breakdown of these intracellular power plants in motor neurons contributes but is the not the sole cause of the disease.

The study is published this month in the Journal of Neuroscience.

Scientists first suspected in the 1990s that mitochondrial malfunction might be involved in ALS when they noticed, looking under the microscope, defects in the skeletal muscle of people with the disease.  Subsequent studies in mSOD1 mice indicated that these intracellular power plants were not working full steam.  But scientists remained unsure whether the failure of mitochondria caused ALS or whether their breakdown was simply a consequence of the disease.

“One of the difficult things that we have been struggling with is the exact role of mitochondria – that’s always been a problem,” says Johns Hopkins University School of Medicine neuroscientist Lee Martin PhD who was not involved in the study.

As early as 1994, however, neuroscientists discovered mitochondrial defects in mSOD1 mice before these animals developed symptoms suggesting that these intracellular power plants at least contributed to the disease.  In 2009, Lee Martin’s team found that bolstering mitochondria by blocking the so-called mitochondrial permeability transition pore (mPTP) significantly delayed the onset of the disease in mice.  And last July, University of Montreal researchers found that a mitochondrial pile up in motor neurons in these mice occurred before the onset of ALS which might interrupt trafficking of life’s essentials – possibly explaining why motor neurons ultimately die during the course of the disease.

Traffic jam. Mitochondria pileup in motor neurons in mice before ALS onset suggesting that defects in them may contribute to the disease.  Adapted from Vande Velde et al. (2011) PLoS One: e22031.

But although these power outages occurred in the right place and the right time, researchers still could not prove in these mice that mitochondrial breakdown triggered the disease. 

”The problem I think that we were facing is that SOD1 is present abundantly,” explains Manfredi, “so the relative role of mitochondrial localization of SOD1 relative to everything else everywhere else has been difficult to assess.”

Now, Manfredi’s team find that mice which produced mSOD1 only in the intracellular membrane space of mitochondria in certain tissues including skeletal muscle develop both defects in energy production and a 30% motor neuron loss suggesting that albeit weakly such power outages may drive at least some aspects of ALS.  But the team sees no signs of motor neurons unplugging from muscles suggesting that there may be other triggers that together result in the disease.

These findings come at the heels of two previous studies in 2009 that demonstrated mutant SOD1 produced exclusively in the mitochondria of cultured motor neurons made them more susceptible to destruction.

Now, the Weill Cornell team hopes to use these mice to ferret out why these intracellular power plants may fail in people with ALS.  And looking ahead, says Manfredi, these mice could be used to find better drugs to keep the power on in dying motor nerves to slow or stop the progression of the disease.

“I don’t think we are at the stage that we have good mitochondrial drugs,” says Manfredi.   “They target only certain aspects of mitochondrial function.” 

Furthermore, with the growing understanding that there is much more to the disease that simply a power outage, combinatorial treatment strategies for ALS may need to be developed.

“Realistically, I don’t think there is going to be a magic bullet for this disease,” says Martin.  “Targeting mitochondria is only one aspect and there are other aspects that need to be explored.”



Igoudjil, A., Magrané, J., Fischer, L.R., Kim, H.J., Hervias, I., Dumont, M., Cortez, C., Glass, J.D., Starkov, A.A., and Manfredi, G. (2011) In Vivo Pathogenic Role of Mutant SOD1 Localized in the Mitochondrial Intermembrane Space.  Journal of Neuroscience 31(44), 15826-15837. Abstract Full Text (Subscription Required) 

Fischer L.R., Igoudjil, A., Magrané, J., Li, Y., Hansen, J.M., Manfredi, G. and Glass J.D. (2011) SOD1 targeted to the mitochondrial intermembrane space prevents motor neuropathy in the Sod1 knockout mouse.  Brain, 134(1), 196-209. Abstract Full Text (Subscription Required) 

Vande Velde, C. et al. (2011).  Misfolded SOD1 associated with motor neuron mitochondria alters mitochondrial shape and distribution prior to clinical onset.  PLoS One 6(7), e22031. Abstract Full Text

Cozzolino, M., Pesaresi, M.G., Amori, I., Crosio, C., Ferri, A., Nencini, M., and Carri, M.T. (2009). Oligomerization of mutant SOD1 in mitochondria of motorneuronal cellsdrives mitochondrial damage and cell toxicity. Antioxidants and Redox Signaling11, 1547-1558.  Abstract Full Text

Magrané, J., Hervias, I., Henning, M.S., Damiano, M., Kawamata, H., and Manfredi G. (2009). Mutant SOD1 in neuronal mitochondria causes toxicity and mitochondrial dynamics abnormalities. Human Molecular Genetics, 18(23), 4552-4564.  Abstract Full Text

Martin, L.J., Gertz, B., Pan, Y., Price, A.C., Molkentin, J.D., Chang, Q (2009). The mitochondrial permeability transition pore in motor neurons: involvement in the pathobiology of ALS mice.  Experimental Neurobiology, 218(2), 333-346.  Abstract Full Text

Dal Canto M.C. and Gurney M.E. (1994) Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis.  American Journal of Pathology, 145(6), 1271-1279.  Abstract Full Text

Further Reading

Martin, L.J. (2010). The mitochondrial permeability transition pore: a molecular target for amyotrophic lateral sclerosis therapy. Biochimica Biophysica Acta, 1802(1), 186-197.  Abstract |Full Text