title: Mitochondrial permeability transition pore induces mitochondria injury in Huntington disease.
abstract: BACKGROUND
  Mitochondrial impairment has been implicated in the pathogenesis of Huntington's disease (HD). However, how mutant huntingtin impairs mitochondrial function and thus contributes to HD has not been fully elucidated. In this study, we used striatal cells expressing wild type (STHdhQ7/Q7) or mutant (STHdhQ111/Q111) huntingtin protein, and cortical neurons expressing the exon 1 of the huntingtin protein with physiological or pathological polyglutamine domains, to examine the interrelationship among specific mitochondrial functions.
  
  
  RESULTS
  Depolarization induced by KCl resulted in similar changes in calcium levels without compromising mitochondrial function, both in wild type and mutant cells. However, treatment of mutant cells with thapsigargin (a SERCA antagonist that raises cytosolic calcium levels), resulted in a pronounced decrease in mitochondrial calcium uptake, increased production of reactive oxygen species (ROS), mitochondrial depolarization and fragmentation, and cell viability loss. The mitochondrial dysfunction in mutant cells was also observed in cortical neurons expressing exon 1 of the huntingtin protein with 104 Gln residues (Q104-GFP) when they were exposed to calcium stress. In addition, calcium overload induced opening of the mitochondrial permeability transition pore (mPTP) in mutant striatal cells. The mitochondrial impairment observed in mutant cells and cortical neurons expressing Q104-GFP was prevented by pre-treatment with cyclosporine A (CsA) but not by FK506 (an inhibitor of calcineurin), indicating a potential role for mPTP opening in the mitochondrial dysfunction induced by calcium stress in mutant huntingtin cells.
  
  
  CONCLUSIONS
  Expression of mutant huntingtin alters mitochondrial and cell viability through mPTP opening in striatal cells and cortical neurons.
authors: Department of Anesthesiology, University of Rochester Medical Center, 601 Elmwood Ave, Box 604 (for courier: Rm 4-6314), Rochester, NY 14642, USA. rquintanilla@med.puc.cl.
authors: Rodrigo A
authors: RA
authors: Quintanilla
authors: Youngnam N
authors: YN
authors: Jin
authors: Rommy
authors: R
authors: von Bernhardi
authors: Gail V W
authors: GV
authors: Johnson
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species