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J. Biol. Chem., Vol. 280, Issue 35, 30773-30782, September 2, 2005

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Mitochondrial Respiration and ATP Production Are Significantly Impaired in Striatal Cells Expressing Mutant Huntingtin^*

Tamara Milakovic and Gail V. W. Johnson

From the Department of Psychiatry, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017

There is significant evidence that energy production impairment and mitochondrial dysfunction play a role in the pathogenesis of Huntington disease. Nonetheless, the specific mitochondrial defects due to the presence of mutant huntingtin have not been fully elucidated. To determine the effects of mutant huntingtin on mitochondrial energy production, a thorough analysis of respiration, ATP production, and functioning of the respiratory complexes was carried out in clonal striatal cells established from Hdh^Q7 (wild-type) and Hdh^Q111 (mutant huntingtin knock-in) mouse embryos. Mitochondrial respiration and ATP production were significantly reduced in the mutant striatal cells compared with the wild-type cells when either glutamate/malate or succinate was used as the substrate. However, mitochondrial respiration was similar in the two cell lines when the artificial electron donor TMPD/ascorbate, which feeds into complex IV, was used as the substrate. The attenuation of mitochondrial respiration and ATP production when either glutamate/malate or succinate was used as the substrate was not due to impairment of the respiratory complexes, because their activities were equivalent in both cell lines. Intriguingly, in the striatum of presymptomatic and pathological grade 1 Huntington disease cases there is also no impairment of mitochondrial complexes I–IV (Guidetti, P., Charles, V., Chen, E. Y., Reddy, P. H., Kordower, J. H., Whetsell, W. O., Jr., Schwarcz, R., and Tagle, D. A. (2001) Exp. Neurol. 169, 340–350). To our knowledge, this is the first comprehensive analysis of the effects of physiological levels of mutant huntingtin on mitochondrial respiratory function within an appropriate cellular context. These findings demonstrate that the presence of mutant huntingtin impairs mitochondrial ATP production through one or more mechanisms that do not directly affect the function of the respiration complexes.

Received for publication, April 29, 2005 , and in revised form, June 17, 2005.

^* This work was supported by National Institutes of Health Grant NS41744. 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.

To whom correspondence should be addressed: Dept. of Psychiatry, 1720 7th Ave., South, SC1061, University of Alabama at Birmingham, Birmingham, AL 35294-0017. Tel.: 205-934-2465; Fax: 205-934-2500; E-mail: gvwj{at}uab.edu.

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