Calcium homeostasis and mitochondrial dysfunction in striatal neurons of Huntington disease.
Dysfunctions of Ca2+ homeostasis and of mitochondria have been studied in immortalized striatal cells from a commonly used Huntington disease mouse model. Transcriptional changes in the components of the phosphatidylinositol cycle and in the receptors for myo-inositol trisphosphate-linked agonists have been found in the cells and in the striatum of the parent Huntington disease mouse. The overall result of the changes is to delay myo-inositol trisphosphate production and to decrease basal Ca2+ in mutant cells. When tested directly, mitochondria in mutant cells behave nearly normally, but are unable to handle large Ca2+ loads. This appears to be due to the increased Ca2+ sensitivity of the permeability transition pore, which dissipates the membrane potential, prompting the release of accumulated Ca2+. Harmful reactive oxygen species, which are produced by defective mitochondria and may in turn stress them, increase in mutant cells, particularly if the damage to mitochondria is artificially exacerbated, for instance with complex II inhibitors. Mitochondria in mutant cells are thus peculiarly vulnerable to stresses induced by Ca2+ and reactive oxygen species. The observed decrease of cell Ca2+ could be a compensatory attempt to prevent the Ca2+ stress that would irreversibly damage mitochondria and eventually lead to cell death.
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D002461:Cell Line, Transformed; D002463:Cell Membrane Permeability / Q000235:genetics; D004195:Disease Models, Animal; D006706:Homeostasis / Q000235:genetics; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007295:Inositol Phosphates / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*
D007295:Inositol Phosphates; D017382:Reactive Oxygen Species; C092449:inositol 1,2,3-trisphosphate; D002118:Calcium