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J. Biol. Chem., Vol. 281, Issue 46, 34785-34795, November 17, 2006

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Mutant Huntingtin Expression Induces Mitochondrial Calcium Handling Defects in Clonal Striatal Cells

FUNCTIONAL CONSEQUENCES^*

From the Department of Psychiatry, University of Alabama at Birmingham, Birmingham, Alabama 35294

Huntington disease (HD) is caused by a pathological elongation of CAG repeats in the huntingtin protein gene and is characterized by atrophy and neuronal loss primarily in the striatum. Mitochondrial dysfunction and impaired Ca²⁺ homeostasis in HD have been suggested previously. Here, we elucidate the effects of Ca²⁺ on mitochondria from the wild type (STHdh^Q7/Q7) and mutant (STHdh^Q111/Q111) huntingtin-expressing cells of striatal origin. When treated with increasing Ca²⁺ concentrations, mitochondria from mutant huntingtin-expressing cells showed enhanced sensitivity to Ca²⁺, as they were more sensitive to Ca²⁺-induced decreases in state 3 respiration and m, than mitochondria from wild type cells. Further, mutant huntingtin-expressing cells had a reduced mitochondrial Ca²⁺ uptake capacity in comparison with wild type cells. Decreases in state 3 respiration were associated with increased mitochondrial membrane permeability. The m defect was attenuated in the presence of ADP and the decreases in Ca²⁺ uptake capacity were abolished in the presence of Permeability Transition Pore (PTP) inhibitors. These findings clearly indicate that mutant huntingtin-expressing cells have mitochondrial Ca²⁺ handling defects that result in respiratory deficits and that the increased sensitivity to Ca²⁺ induced mitochondrial permeabilization maybe a contributing mechanism to the mitochondrial dysfunction in HD.

Received for publication, April 21, 2006 , and in revised form, August 2, 2006.

^* This study was supported by National Institutes of Health Grant NS041744. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Psychiatry, 1720 7th Ave. South, SC 1061, University of Alabama at Birmingham, Birmingham, AL 35294-0017. Tel.: 205-934-2465; Fax: 205-934-3709; E-mail: gvwj{at}uab.edu.

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