Human Molecular Genetics Advance Access published online on May 26, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh162
© 2004 by Oxford University Press
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1 Department of Psychiatry, University of Alabama at Birmingham, Birmingham, AL 35294, USA
* To whom correspondence should be addressed. E-mail: mlesort{at}uab.edu.
Huntington's disease (HD) is initiated by an abnormally expanded polyglutamine stretch in the huntingtin protein conferring a novel property on the protein that leads to the loss of striatal neurons. Defects in mitochondrial function have been implicated in the pathogenesis of HD. Here we have examined the hypothesis that the mutant huntingtin protein may directly interact with the mitochondrion and affect its function. In human neuroblastoma cells and clonal striatal cells established from HdhQ7 (wild-type) and HdhQ111 (mutant) homozygote mouse knock-in embryos, huntingtin was present in a purified mitochondrial fraction. Sub-fractionation of the mitochondria and limited trypsin digestion of the organelle demonstrated that huntingtin was associated with the outer mitochondrial membrane. We further demonstrated that a recombinant truncated mutant huntingtin protein, but not a wild type, directly induced mitochondrial permeability transition (MPT) pore opening in isolated mouse liver mitochondria, an effect that was completely prevented by cyclosporin A and ATP. Importantly, the mutant huntingtin protein decreased significantly the calcium threshold necessary to trigger MPT pore opening. We found a similar increased susceptibility to the calcium-induced MPT in liver mitochondria isolated from a knock-in HD mouse model. The mutant huntingtin protein-induced MPT pore opening was accompanied by a significant release of cytochrome c, an effect completely inhibited by cyclosporin A. These findings suggest that the development of specific MPT inhibitors may be an interesting therapeutic avenue to delay the onset of HD.
Article
Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release
2 Molecular Neurogenetics Unit, Massachusetts General Hospital, Building 149,13th St, Charlestown, MA 02129, USA
3 Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
4 Department of Psychiatry and Behavioral Neurobiology 1720, 7th Avenue South, SC1079, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA
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