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Polyglutamine expansion inhibits respiration by increasing reactive oxygen species in isolated mitochondria
Kasturi L Puranam1, Guanghong Wu, Warren J Strittmatter
1Deane Laboratory, Department of Medicine, Division of Neurology, Duke University Medical Center, Durham, NC 27710, USA.
Abstract:
Huntington's disease results from expansion of the polyglutamine (PolyQ) domain in the huntingtin protein. Although the cellular mechanism by which pathologic-length PolyQ protein causes neurodegeneration is unclear, mitochondria appear central in pathogenesis. We demonstrate in isolated mitochondria that pathologic-length PolyQ protein directly inhibits ADP-dependent (state 3) mitochondrial respiration. Inhibition of mitochondrial respiration by PolyQ protein is not due to reduction in the activities of electron transport chain complexes, mitochondrial ATP synthase, or the adenine nucleotide translocase. We show that pathologic-length PolyQ protein increases the production of reactive oxygen species in isolated mitochondria. Impairment of state 3 mitochondrial respiration by PolyQ protein is reversed by addition of the antioxidants N-acetyl-L-cysteine or cytochrome c. We propose a model in which pathologic-length PolyQ protein directly inhibits mitochondrial function by inducing oxidative stress.
Insights
Pathologic-length polyglutamine (PolyQ) protein in Huntington's disease directly impairs mitochondrial respiration and increases oxidative stress. Antioxidants can reverse this mitochondrial dysfunction, suggesting a key role for oxidative damage.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Genetics
Background:
- Huntington's disease is a neurodegenerative disorder caused by expanded polyglutamine (PolyQ) tracts in the huntingtin protein.
- The precise cellular mechanisms driving neurodegeneration in Huntington's disease remain elusive, but mitochondria are implicated.
Purpose of the Study:
- To investigate the direct impact of pathologic-length PolyQ protein on mitochondrial function.
- To elucidate the role of mitochondria in the pathogenesis of Huntington's disease.
Main Methods:
- Isolated mitochondria were used to assess ADP-dependent (state 3) respiration.
- Activities of electron transport chain complexes, ATP synthase, and adenine nucleotide translocase were measured.
- Reactive oxygen species (ROS) production was quantified.
- The effects of antioxidants N-acetyl-L-cysteine and cytochrome c were evaluated.
Main Results:
- Pathologic-length PolyQ protein directly inhibited state 3 mitochondrial respiration.
- This inhibition was not caused by reduced activity of key mitochondrial components.
- PolyQ protein significantly increased ROS production in isolated mitochondria.
- Antioxidant treatment reversed the impairment of state 3 respiration.
Conclusions:
- Pathologic-length PolyQ protein directly impairs mitochondrial respiration.
- Oxidative stress induced by PolyQ protein is a key mechanism in mitochondrial dysfunction in Huntington's disease.
- Targeting oxidative stress may offer therapeutic potential for Huntington's disease.
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