TY - JOUR
T1 - Increased susceptibility of striatal mitochondria to calcium-induced permeability transition
AU - Brustovetsky, Nickolay
AU - Brustovetsky, Tatiana
AU - Purl, Kevin J.
AU - Capano, Michela
AU - Crompton, Martin
AU - Dubinsky, Janet M.
PY - 2003/6/15
Y1 - 2003/6/15
N2 - Mitochondria were simultaneously isolated from striatum and cortex of adult rats and compared in functional assays for their sensitivity to calcium activation of the permeability transition. Striatal mitochondria showed an increased dose-dependent sensitivity to Ca2+ compared with cortical mitochondria, as measured by mitochondrial depolarization, swelling, Ca2+ uptake, reactive oxygen species production, and respiration. Ratios of ATP to ADP were lower in striatal mitochondria exposed to calcium despite equal amounts of ADP and ATP under respiring and nonrespiring conditions. The Ca2+-induced changes were inhibited by cyclosporin A or ADP. These responses are consistent with Ca2+ activation of both low and high permeability pathways constituting the mitochondrial permeability transition. In addition to the striatal supersensitivity to induction of the permeability transition, cyclosporin A inhibition was less potent in striatal mitochondria. Immunoblots indicated that striatal mitochondria contained more cyclophilin D than cortical mitochondria. Thus striatal mitochondria may be selectively vulnerable to the permeability transition. Subsequent mitochondrial dysfunction could contribute to the initial toxicity of striatal neurons in Huntington's disease.
AB - Mitochondria were simultaneously isolated from striatum and cortex of adult rats and compared in functional assays for their sensitivity to calcium activation of the permeability transition. Striatal mitochondria showed an increased dose-dependent sensitivity to Ca2+ compared with cortical mitochondria, as measured by mitochondrial depolarization, swelling, Ca2+ uptake, reactive oxygen species production, and respiration. Ratios of ATP to ADP were lower in striatal mitochondria exposed to calcium despite equal amounts of ADP and ATP under respiring and nonrespiring conditions. The Ca2+-induced changes were inhibited by cyclosporin A or ADP. These responses are consistent with Ca2+ activation of both low and high permeability pathways constituting the mitochondrial permeability transition. In addition to the striatal supersensitivity to induction of the permeability transition, cyclosporin A inhibition was less potent in striatal mitochondria. Immunoblots indicated that striatal mitochondria contained more cyclophilin D than cortical mitochondria. Thus striatal mitochondria may be selectively vulnerable to the permeability transition. Subsequent mitochondrial dysfunction could contribute to the initial toxicity of striatal neurons in Huntington's disease.
KW - Brain mitochondria
KW - Cyclophilin D
KW - Huntington's disease
KW - Neurotoxicity
KW - Permeability transition
KW - Regional differences
UR - http://www.scopus.com/inward/record.url?scp=0037741021&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037741021&partnerID=8YFLogxK
U2 - 10.1523/jneurosci.23-12-04858.2003
DO - 10.1523/jneurosci.23-12-04858.2003
M3 - Article
C2 - 12832508
AN - SCOPUS:0037741021
SN - 0270-6474
VL - 23
SP - 4858
EP - 4867
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 12
ER -