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Trends Neurosci. 2008 Dec;31(12):609-16. doi: 10.1016/j.tins.2008.09.004. Epub 2008 Oct 24.

Mutant huntingtin and mitochondrial dysfunction.

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University of Central Florida, Burnett School of Biomedical Sciences, College of Medicine, 4000 Central Florida Boulevard, Orlando, FL 32816, USA.


Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder that gradually robs affected individuals of memory, cognitive skills and normal movements. Although research has identified a single faulty gene, the huntingtin gene, as the cause of the disease, a cure remains elusive. Strong evidence indicates that mitochondrial impairment plays a key part in HD pathogenesis. Here, we highlight how mutant huntingtin (mtHtt) might cause mitochondrial dysfunction by either perturbing transcription of nuclear-encoded mitochondrial proteins or by direct interaction with the organelle and modulation of respiration, mitochondrial membrane potential and Ca(2+) buffering. In addition, we propose that mtHtt might convey its neurotoxicity by evoking defects in mitochondrial dynamics, organelle trafficking and fission and fusion, which, in turn, might result in bioenergetic failure and HD-linked neuronal dysfunction and cell death. Finally, we speculate how mitochondria might dictate selective vulnerability of long projection neurons, such as medium spiny neurons, which are particularly affected in HD.

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