Extended polyglutamine repeats trigger a feedback loop involving the mitochondrial complex III, the proteasome and huntingtin aggregates.
Mitochondrial abnormalities represent a major cytopathology in Huntington's disease (HD), a fatal neurodegenerative disease caused by CAG repeat expansions in the gene encoding huntingtin (Htt). In the present study, we investigated whether defects in the mitochondrial respiratory function are consequences of the expression of mutant Htt or they promote the formation of Htt aggregates. To take advantage of existing mitochondrial DNA mutants, we developed human osteosarcoma 143B cells expressing mutant Htt in an inducible manner and found that cells expressing mutant Htt but not wild-type Htt 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 Htt aggregates. This complex III-mediated modulation of Htt aggregates was also observed in a neuronal progenitor RN33B cell line transduced by lentivirus carrying mutant Htt. This effect of complex III inhibition on the Htt 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 Htt aggregates. Our results suggest that therapeutic interventions targeting complex III and/or proteasome could ameliorate the progress of HD.
Fukui
Hirokazu
H
Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Moraes
Carlos T
CT
D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D014450:Electron Transport Complex III / Q000378:metabolism*; D003576:Electron Transport Complex IV / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011190:Potassium Cyanide / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011489:Protein Denaturation; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion
D000975:Antioxidants; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011993:Recombinant Fusion Proteins; C097188:polyglutamine; D003576:Electron Transport Complex IV; D046988:Proteasome Endopeptidase Complex; D014450:Electron Transport Complex III; D011190:Potassium Cyanide; D000111:Acetylcysteine