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J. Biol. Chem., Vol. 283, Issue 9, 5780-5789, February 29, 2008

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Calcium Homeostasis and Mitochondrial Dysfunction in Striatal Neurons of Huntington Disease^*

Dmitry Lim, Laura Fedrizzi^¶, Marzia Tartari^||, Chiara Zuccato^||, Elena Cattaneo^||, Marisa Brini^¶, and Ernesto Carafoli¹

From the Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padua, Italy, the Departments of Biochemistry and ^¶Experimental Veterinary Science, University of Padua, Viale Colombo 3, 35131 Padua, Italy, and the ^||Department of Pharmacological Sciences, University of Milan, Milan, Italy

Dysfunctions of Ca²⁺ homeostasis and of mitochondria have been studied in immortalized striatal cells from a commonly used Huntington disease mouse model. Transcriptional changes in the components of the phosphatidylinositol cycle and in the receptors for myo-inositol trisphosphate-linked agonists have been found in the cells and in the striatum of the parent Huntington disease mouse. The overall result of the changes is to delay myo-inositol trisphosphate production and to decrease basal Ca²⁺ in mutant cells. When tested directly, mitochondria in mutant cells behave nearly normally, but are unable to handle large Ca²⁺ loads. This appears to be due to the increased Ca²⁺ sensitivity of the permeability transition pore, which dissipates the membrane potential, prompting the release of accumulated Ca²⁺. Harmful reactive oxygen species, which are produced by defective mitochondria and may in turn stress them, increase in mutant cells, particularly if the damage to mitochondria is artificially exacerbated, for instance with complex II inhibitors. Mitochondria in mutant cells are thus peculiarly vulnerable to stresses induced by Ca²⁺ and reactive oxygen species. The observed decrease of cell Ca²⁺ could be a compensatory attempt to prevent the Ca²⁺ stress that would irreversibly damage mitochondria and eventually lead to cell death.

Received for publication, June 7, 2007 , and in revised form, December 17, 2007.

^* This work was supported by the European Union FP6 Integrated Project NeuroNE (to E. C. and E. C.), Telethon Foundation Project GGP04169 (to M. B.), and the Italian Ministry of University and Research (PRIN 2005, to M. B. and the FIRB 2001, to E. C.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1.

¹ To whom correspondence should be addressed: Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padua, Italy. Tel.: 39-049-8276137; Fax: 39-049-8276125; E-mail: ernesto.carafoli{at}unipd.it.

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