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Human Molecular Genetics Advance Access originally published online on May 26, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 14 1407-1420
DOI: 10.1093/hmg/ddh162
Human Molecular Genetics, Vol. 13, No. 14 © Oxford University Press 2004; all rights reserved

Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release

Yeun Su Choo1, Gail V.W. Johnson1, Marcy MacDonald3, Peter J. Detloff2 and Mathieu Lesort1,*

1Department of Psychiatry, 2Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA and 3Molecular Neurogenetics Unit, Massachusetts General Hospital, Building 149, 13th Street Charlestown, MA 02129, USA

Received January 6, 2004; Accepted May 14, 2004

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. Subfractionation 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 prevented completely by cyclosporin A (CSA) and ATP. Importantly, the mutant huntingtin protein significantly decreased the Ca2+ 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 CSA. These findings suggest that the development of specific MPT inhibitors may be an interesting therapeutic avenue to delay the onset of HD.

* To whom correspondence should be addressed at: Department of Psychiatry and Behavioral Neurobiology, 1720, 7th Avenue South, SC1079, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA. Tel: +1 2059342442; Fax: +1 2059343709; Email: mlesort{at}uab.edu


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