Take a deep breath. Mitochondrial respiration problems could be central to Parkinson disease (PD) pathology. That’s according to Nils-Göran Larsson and colleagues at the Karolinska Institute, Stockholm, Sweden. In this week’s PNAS online, the researchers describe how mitochondrial deficiency in midbrain dopaminergic neurons mimics this devastating disease in mice rather faithfully, with late-onset and slowly progressing neurological symptoms. The results suggest that damage to mitochondria is sufficient to cause Parkinson’s-like neurodegeneration.

Mitochondria are the cell’s generators, pumping out heat and the high-energy compounds that drive power-hungry processes such as muscle contraction, protein synthesis, and neurotransmitter release—neurons are laden with the tiny organelles. This is not the first time mitochondria have been linked to neurodegenerative diseases. Toxic reactive oxygen species generated by the mitochondrial respiratory chain and mutations in mitochondrial DNA (mtDNA) are both suspects in Parkinson disease pathology (see ARF related news story). Yet it has been difficult to determine with certainty if mitochondrial damage is the cause or merely an effect of PD. Even in the case of MPTP, a mitochondrial toxin responsible for some rare cases of Parkinson’s, it is unclear if the disease directly results from damage to mitochondria in midbrain dopaminergic (DA) neurons that are primarily affected by the disease, or whether other MPTP toxicities or damage to other areas of the brain play a role. The strength of this new study is that it specifically probes the role of those DA neurons.

Larsson and colleagues took advantage of the widely used Cre-lox recombination system that selectively removes pieces of DNA from the genome. First author Mats Ekstrand and colleagues trained the system on the gene for mitochondrial transcription factor A (Tfam). Tfam is essential for healthy mitochondria because it not only controls the amount of DNA made in each organelle, but, as a master transcription factor, it also controls expression of mitochondrial genes. The mitochondrial genome encodes 13 key subunits of the respiratory chain (most other mitochondrial genes are actually encoded in the nucleus), and therefore loss of Tfam might be expected to have serious consequences for oxidative respiration. And that’s just what Ekstrand and colleagues found.

The scientists crossed mice expressing Cre recombinase under the control of the dopamine transporter gene with mice expressing Lox-flanked Tfam alleles. The resulting MitoPark mouse strain has a homozygous disruption of Tfam in midbrain DA neurons and an unhealthy loss of cytochrome c oxidase (Cox) to boot. Cox catalyzes the very last of the respiratory chain reactions, and without it the complete pathway slows to a crawl.

What are the physiological consequences of slowing down respiration in these mitochondria? Young mice appeared to cope just fine; however, by 14-15 weeks they began to tremble, twitch, and their limbs became rigid—all tell-tale signs of parkinsonism. After a single dose of L-dopa, the treatment of choice for people with Parkinson’s, the mice improved considerably. However, much like in human cases, the drug proved less and less effective as the animals aged.

The symptoms can be explained by a gradual loss of DA neurons in the dorsolateral striatum beginning around week 12. This was more apparent in the substantia nigra, the area most badly affected in Parkinson’s patients. Even earlier, at about 6 weeks, the researchers detected the accumulation of cytoplasmic aggregates. These did not contain α-synuclein, a major component of the Lewy bodies found in the neurons of people with PD. The exact nature of the aggregates is unclear, but the fact that a double membrane reminiscent of the mitochondrial membrane surrounded some of them suggests that they may represent mitochondrial degradation products. Indeed, the authors speculate that “…reduced mtDNA expression may lead to an aggregation of nucleus-encoded proteins in the mitochondria of DA neurons, and that that event could initiate an aggregation process also involving non-mitochondrial proteins.”

The similarities between this new mouse phenotype and Parkinson’s pathology suggest that the disease may, at least in some cases, start in the mitochondria. Whether this means reactive oxygen species play a role is unclear. The MitoPark mouse may help answer this vexing question about the disease.—Tom Fagan


  1. This paper supports the longstanding hypothesis that mitochondrial derangements are sufficient to cause cell death in nigral neurons, which may be an important clue for Parkinson disease. There is some later cell loss in the ventral tegmental area, which differs from Parkinson disease and from other models, and presumably if Tfam had been knocked out in other neurons, as well, one might see loss in other brain regions. We cannot quite conclude from these experiments alone that mitochondrial damage is sufficient to cause PD. But when added to the emerging evidence from genetic parkinsonism, where mitochondrial function is also implicated, the results suggest that mitochondrial function is important for maintenance of neuronal function and survival.

    These mice obviously have great potential utility in testing therapies aimed at preventing the symptoms of PD. Ekstrand et al. show that the mice respond to the major (symptomatic) therapy available for PD, that is, L-dopa. It is very interesting to see that there is an aging component to the responsiveness to L-dopa, which might be important for other therapies in the future. Also interesting is the observation of inclusion bodies in the dying cells. Showing how careful a study this is, Ekstrand et al. prove that these are not α-synuclein-positive despite one polyclonal antibody to synuclein labeling them. Presumably, the inclusion bodies are related to mitochondria, which might be a very novel part of the inclusion body formation process and worth pursuing in the future.

    View all comments by Mark Cookson
  2. This is a very interesting paper. It clearly shows that select loss of mitochondrial function in midbrain dopaminergic neurons can lead to a progressive respiratory chain deficiency, which then leads to inclusion formation and loss of dopaminergic neurons. The study is very well done. The authors have characterized the mice behaviorally. They have shown motor deficits, which respond to L-dopa therapy. The progressive development of the loss of midbrain neurons had several of the key features of PD. It showed adult-onset neurodegeneration, slowly progressive clinical course, earlier onset of cell death, and more extensive cell death in the substantia nigra than the ventral tegmental area, as well as the development of inclusions. The inclusions proved not to be α-synuclein-positive. They contained mitochondrial proteins as well as membrane components.

    The strength of this is that it is a slowly evolving model of PD. It also ties in to recently observed marked increases in mitochondrial deletions in the substantia nigra, which occur in laser-dissected individual dopaminergic neurons of PD patients (Bender et al., 2006). The increase in deletions in these neurons is sufficient to cause cell death in other circumstances. The present findings, therefore, support these observations as being of pathophysiologic importance in both normal aging and in the pathogenesis of PD. The increase in deletions in the human patients may be a consequence of oxidative stress related to dopamine turnover.

    The one caveat I have about the present paper is that the group created the mitochondrial dysfunction specifically in dopamine neurons only. It would have been interesting to determine if the same thing occurs in other neurons, or with a more generalized mitochondrial dysfunction of brain, and whether this would result in a relatively selective vulnerability of dopaminergic neurons. Nevertheless, this model will be highly useful for testing a number of therapeutic interventions.


    . High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet. 2006 May;38(5):515-7. PubMed.

    View all comments by M. Flint Beal
  3. It's of interest these signs of Tfam deficiency occur with age. SIRT1 is an activator of peroxisome proliferation-activated receptor-γ coactivator-1 α (PGC-1α) which has been shown to increase Tfam (1,2). Perhaps the changes seen in this model may not only occur in Parkinson's but may also reflect the aging process. It would be interesting to see whether resveratrol, an activator of SIRT1 and PGC-1α, may prevent or delay the signs of Parkinson's reported to occur in these mice at 14-15 weeks. The study by Lee and colleagues (3) finding reduced Tfam in the fetus with DS would have me question why more extensive neuronal loss in the substantia nigra is not reported in that condition. Mann et al. (4) report loss of pigmented dopaminergic nerve cells from the ventral tegmental area in patients with Down syndrome at middle age.


    . Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006 Dec 15;127(6):1109-22. PubMed.

    . Impaired coactivator activity of the Gly482 variant of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) on mitochondrial transcription factor A (Tfam) promoter. Biochem Biophys Res Commun. 2006 Jun 9;344(3):708-12. PubMed.

    . Expression of the mitochondrial ATPase6 gene and Tfam in Down syndrome. Mol Cells. 2003 Apr 30;15(2):181-5. PubMed.

    . Dopaminergic neurotransmitter systems in Alzheimer's disease and in Down's syndrome at middle age. J Neurol Neurosurg Psychiatry. 1987 Mar;50(3):341-4. PubMed.

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News Citations

  1. DNA Deletions Sap Mitochondria in Parkinson Neurons

Further Reading

Primary Papers

  1. . Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1325-30. PubMed.