title: Polyglutamine expansion inhibits respiration by increasing reactive oxygen species in isolated mitochondria.
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.
authors.affiliation: Deane Laboratory, Department of Medicine, Division of Neurology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Kasturi L
authors.initials: KL
authors.lastname: Puranam
authors.forename: Guanghong
authors.initials: G
authors.lastname: Wu
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Strittmatter
authors.forename: James R
authors.initials: JR
authors.lastname: Burke
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000225:Adenine / Q000737:chemistry; D000244:Adenosine Diphosphate / Q000737:chemistry*; D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism / Q000494:pharmacology; D004579:Electron Transport; D004591:Electrophoresis, Polyacrylamide Gel; D008099:Liver / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000378:metabolism; D018384:Oxidative Stress; D010101:Oxygen Consumption; D010455:Peptides / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D010455:Peptides; D017382:Reactive Oxygen Species; C097188:polyglutamine; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D000226:Mitochondrial ADP, ATP Translocases; D009245:NADH Dehydrogenase; D025261:Mitochondrial Proton-Translocating ATPases; D000225:Adenine; D000111:Acetylcysteine