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Human Molecular Genetics Advance Access published online on March 13, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm023
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Extended polyglutamine repeats trigger a feedback loop involving the mitochondrial complex III, the proteasome, and huntingtin aggregates

Hirokazu Fukui1 and Carlos T. Moraes1,2,3,*

1 Neuroscience Program, University of Miami Miller School of Medicine, Miami, Florida, 33136 2 Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, 33136 3 Department of Cell Biology & Anatomy, University of Miami Miller School of Medicine, Miami, Florida, 33136

* Corresponding author: Carlos T. Moraes, Ph.D., Department of Neurology, 1095 NW 14th Terrace, Miami, FL 33136, Tel. (305) 243-5858; Fax. (305) 243-3914; E-mail: cmoraes{at}med.miami.edu

Received November 21, 2006; Revised January 22, 2007; Accepted February 9, 2007

Mitochondrial abnormalities represent a major cytopathology in Huntington's disease, a fatal neurodegenerative disease caused by CAG repeat expansions in the gene encoding huntingtin. In the present study, we investigated whether defects in the mitochondrial respiratory function are consequences of the expression of mutant huntingtin or whether they promote the formation of huntingtin aggregates. To take advantage of existing mitochondrial DNA mutants, we developed human osteosarcoma 143B cells expressing mutant huntingtin in an inducible manner and found that cells expressing mutant huntingtin but not wild type huntingtin exhibited a reduced activity of Complex III and an increased activity of Complex IV. Conversely, pharmacological treatments that inhibited Complex III activity significantly promoted the formation of huntingtin aggregates. This Complex III-mediated modulation of huntingtin aggregates was also observed in the neural precursor cell line RN33B transduced by lentivirus carrying mutant huntingtin. This effect of Complex III inhibition on the huntingtin aggregates appeared to be mediated by the inhibition of proteasome activity but not by ATP depletion or production of reactive oxygen species. Accordingly, Complex III mutant cells also showed decreased proteasome activity. These results suggest the presence of a feedback system connecting the mitochondrial respiratory Complex III and the production of huntingtin aggregates. Our results suggest that therapeutic interventions targeting Complex III and/or proteasome could ameliorate the progress of Huntington's disease.


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