title: Oxidative metabolism and Ca2+ handling in isolated brain mitochondria and striatal neurons from R6/2 mice, a model of Huntington's disease.
abstract: Alterations in oxidative metabolism and defects in mitochondrial Ca2+handling have been implicated in the pathology of Huntington's disease (HD), but existing data are contradictory. We investigated the effect of human mHtt fragments on oxidative metabolism and Ca2+handling in isolated brain mitochondria and cultured striatal neurons from the R6/2 mouse model of HD. Non-synaptic and synaptic mitochondria isolated from the brains of R6/2 mice had similar respiratory rates and Ca2+uptake capacity compared with mitochondria from wild-type (WT) mice. Respiratory activity of cultured striatal neurons measured with Seahorse XF24 flux analyzer revealed unaltered cellular respiration in neurons derived from R6/2 mice compared with neurons from WT animals. Consistent with the lack of respiratory dysfunction, ATP content of cultured striatal neurons from R6/2 and WT mice was similar. Mitochondrial Ca2+accumulation was also evaluated in cultured striatal neurons from R6/2 and WT animals. Our data obtained with striatal neurons derived from R6/2 and WT mice show that both glutamate-induced increases in cytosolic Ca2+and subsequent carbonilcyanide p-triflouromethoxyphenylhydrazone-induced increases in cytosolic Ca2+were similar between WT and R6/2, suggesting that mitochondria in neurons derived from both types of animals accumulated comparable amounts of Ca2+Overall, our data argue against respiratory deficiency and impaired Ca2+handling induced by human mHtt fragments in both isolated brain mitochondria and cultured striatal neurons from transgenic R6/2 mice.
authors.affiliation: Department of Pharmacology and Toxicology.
authors.forename: James
authors.initials: J
authors.lastname: Hamilton
authors.affiliation: Department of Pharmacology and Toxicology.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Pellman
authors.affiliation: Department of Pharmacology and Toxicology.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Brustovetsky
authors.affiliation: Department of Biochemistry and Molecular Biology.|Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.affiliation: Department of Pharmacology and Toxicology nbrous@iu.edu.|Stark Neuroscience Research InstituteIndiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Nickolay
authors.initials: N
authors.lastname: Brustovetsky
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D019069:Cell Respiration; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein / Q000378:metabolism*; D006816:Huntington Disease / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D017072:Neostriatum / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D010100:Oxygen