Mutant huntingtin and mitochondrial dysfunction

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Humans
  • Huntingtin Protein
  • Mitochondria / pathology
  • Mitochondria / physiology
  • Mitochondrial Diseases / genetics*
  • Models, Biological
  • Mutation*
  • Nerve Tissue Proteins / genetics*
  • Nuclear Proteins / genetics*


  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins