In vitro effects of polyglutamine tracts on Ca2+-dependent depolarization of rat and human mitochondria: relevance to Huntington's disease.


Journal Article

The mechanisms by which neurons die in CAG triplet repeat (polyglutamine) disorders, such as Huntington's disease, are uncertain; however, mitochondrial dysfunction and disordered calcium homeostasis have been implicated. We previously demonstrated abnormal mitochondrial calcium handling in Huntington's disease cell lines and transgenic mice. To examine whether these abnormalities might arise in part from direct effects of the expanded polyglutamine tract contained in mutant huntingtin, we have exposed normal rat liver and human lymphoblast mitochondria to glutathione S-transferase fusion proteins containing polyglutamine tracts of 0, 19, or 62 residues. Similar to bovine serum albumin, each of the protein constructs nonspecifically inhibited succinate-supported respiration, independent of polyglutamine tract length. There was a small but significant reduction of mitochondrial membrane potential (state 4) only in the presence of the pathological-length polyglutamine tract. With successive addition of small Ca(2+) aliquots, mitochondria exposed to pathological-length polyglutamine tracts (approximately 5 microM) depolarized much earlier and to a greater extent than those exposed to the other protein constructs. These results suggest that the mitochondrial calcium handling defects seen in Huntington's disease cell lines and transgenic mice may be due, in part, to direct, deleterious effects of mutant huntingtin on mitochondria.

Full Text

Duke Authors

Cited Authors

  • Panov, AV; Burke, JR; Strittmatter, WJ; Greenamyre, JT

Published Date

  • February 1, 2003

Published In

Volume / Issue

  • 410 / 1

Start / End Page

  • 1 - 6

PubMed ID

  • 12559971

Pubmed Central ID

  • 12559971

International Standard Serial Number (ISSN)

  • 0003-9861

Digital Object Identifier (DOI)

  • 10.1016/s0003-9861(02)00585-4


  • eng

Conference Location

  • United States