An advanced online publication in today’s Nature Neuroscience lends support to the hypothesis that mitochondrial damage contributes to the progression of Huntington’s disease.

While it is known that a polyglutamine (polyQ) expansion in the huntingtin (htt) protein is the direct cause of this fatal disorder, just how the mutant protein wreaks havoc on neurons is poorly understood. It is thought that expanded htt, in either soluble form or in cytoplasmic or nuclear inclusions, may mediate pathogenesis by interacting with and disrupting the normal function of other proteins, such as transcription factors (see related news item). Other studies, however, have pointed out deficiencies in mitochondrial respiration in Huntington’s brain tissue, suggesting that damage to these organelles may play a role in disease progression (see Tabrizi et al.).

Timothy Greenamyre and co-workers at Emory University, Atlanta, together with colleagues from Duke University, Durham, North Carolina, and the University of British Columbia, Vancouver, now show that the membranes of mitochondria from Huntington’s patients are susceptible to depolarization. The authors used extra-organellar calcium ions to probe the mitochondrial membrane potential; if the organelles are bathed in sufficient Ca2+ the membranes will depolarize. The researchers found that much less Ca2+ was needed to achieve depolarization of lymphoblast mitochondria from HD patients than for wild-type organelles, and those from juvenile onset HD patients were even more susceptible to the cation.

First author Alexander Panov et al. repeated these experiments using brain mitochondria from transgenic mice expressing varying amounts of human mutant huntingtin, and obtained identical results. They also used electron microscopy to demonstrate that polyQ htt, but not wild-type, associates with mitochondria, suggesting that the protein may have a direct role in destabilizing their membranes, perhaps by acting as ion channels. Mitochondria are also affected in Alzheimer’s disease, (see Mungarro-Menchaca et al. 2002.)

It remains to be seen, however, whether this effect on mitochondria is a primary or secondary one, and whether it can explain the extremely slow onset of Huntington’s disease (see commentary by Elena Cattaneo below).—Tom Fagan


  1. The paper by Panov et al. is absolutely timely. We knew that the mitochondria were involved in HD. We had beautiful evidence that, i.e. animals exposed to systemic injection of a mitochondrial toxin (3-nitropropionic acid) were reproducing neurological deficits similar to those present in HD. However, this evidence was indirect. In other words, we were supposing that 3NP was evoking striatal toxicity by acting along the same pathway(s) or on the same targets as did mutant huntingtin. But we did not know where the precise link was.

    Now this paper shows that mutant but not wild-type huntingtin binds to the mitochondria, whose critical roles in living cells include ATP production, handling calcium, and controlling the activity of specific and potentially harmful enzymes. By binding to mitochondria, mutant huntingtin impairs its functionality, leaving cells in the middle of an earthquake. Changes in calcium homeostasis can activate proteases like the calpains, which cleave other proteins including wild-type huntingtin itself, which we found to be neuroprotective. This double whammy of a toxic mutant protein and loss of function of the wild-type huntingtin leads to disease.

    Panov et al. have beautifully confirmed their studies in three experimental settings, first, after incubation of purified normal mitochondria with mutant huntingtin, second, by analyzing the activity of these organelles isolated from control and transgenic mice overexpressing mutant huntingtin, and third, by studying the mitochondria from lymphoblasts of HD patients.

    Two questions remain unsolved: how can the disease remain latent for approximately the first 35 years of life, and how does the observed dysfunction of the mitochondria cause the selective striatal vulnerability in HD? In their paper the authors show that the mitochondrial dysfunction precedes by months symptom manifestation in mice. Therefore, it may well be that disease onset, as defined clinically, is actually preceded by subtle dysfunctions that accumulate for years and, slowly but relentlessly, bring the individual to a stage when these abnormalities cannot be hidden anymore.

    On the second question, the situation is equally mysterious. As expected, the Panov paper contains no indication that mutant huntingtin binds preferentially to striatal mitochondria, as indeed lymphoblast mitochondria show the same defect. The mutant protein may hamper the activity of several cell types, if not all, but the striatal mitochondria may be more disturbed by their inability to handle calcium properly. The striatum receives an important and specific afferent pathway from the cerebral cortex that releases the potent excitotoxin glutamate. Various data indicate a hyperactivity of this pathway in HD. Altered mitochondrial calcium handling in striatal HD neurons may render neurons unable to process the cortical glutamatergic input correctly.

    It could also be that mitochondrial dysfunction is not the trigger but a consequence of other cellular abnormalities. At this stage of research, any possibility should be taken seriously until we have established a temporal pattern for the various interesting cellular dysfunctions reported by several authors. Among them is the loss of normal huntingtin activity, which also may produce a striatal defect.

    Thorough investigations of disease mechanisms and cooperation between basic and clinical science is necessary if we are to give hopes to those that suffer from Huntington's disease.

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News Citations

  1. Transcriptional Activators Kidnapped by Huntingtin

External Citations

  1. Tabrizi
  2. Mungarro-Menchaca

Further Reading

Primary Papers

  1. . Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines. Nat Neurosci. 2002 Aug;5(8):731-6. PubMed.