title: Iptakalim ameliorates MPP+-induced astrocyte mitochondrial dysfunction by increasing mitochondrial complex activity besides opening mitoK(ATP) channels.
abstract: In addition to the established role of the mitochondrion in energy metabolism, regulation of cell death has been regarded as a major function of this organelle. Our previous studies have demonstrated that iptakalim (IPT), a novel ATP-sensitive potassium channel (K(ATP) channel) opener, protects against 1-methyl-4-phenyl-pyridinium ion (MPP+)-induced astrocyte apoptosis via mitochondria and mitogen-activated protein kinase signal pathways. The present study aimed to investigate whether IPT can protect astrocyte mitochondria against MPP+-induced mitochondrial dysfunction. We showed that treatment with IPT could ameliorate the inhibitory effect of MPP+ on mitochondrial respiration and ATP production by using mitochondrial complex I-supported substrates. IPT could also inhibit the increased production of mitochondrial reactive oxygen species (ROS) and the release of cytochrome c from mitochondria induced by MPP+. However, mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel blocker 5-hydroxydecanoate (5-HD) could partly abolish all of the above effects of IPT. Because mitochondrial complex dysfunction impairs mitochondrial respiration and ATP production, a further experiment was undertaken to study the effects of IPT on the activity of mitochondrial complex (COX) I and COX IV. It was found that IPT inhibited the decrease in mitochondrial COX I and COX IV activity induced by MPP+, but 5-HD failed to abolish these effects. Taken together, these findings suggest that IPT may protect astrocyte mitochondrial function by regulating complex activity in addition to opening mitoK(ATP) channels.
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, Peoples Republic of China.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Ding
authors.forename: Fang
authors.initials: F
authors.lastname: Zhou
authors.forename: Zhi-Yuan
authors.initials: ZY
authors.lastname: Wang
authors.forename: Xi-Qiao
authors.initials: XQ
authors.lastname: Zhou
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D015153:Blotting, Western; D019069:Cell Respiration / Q000502:physiology; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D042967:Electron Transport Complex I / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology; D015221:Potassium Channels / Q000819:agonists / Q000378:metabolism*; D011437:Propylamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C502260:N-(1-methylethyl)-1,1,2-trimethylpropylamine; D009498:Neurotoxins; D015221:Potassium Channels; D011437:Propylamines; D017382:Reactive Oxygen Species; C117780:mitochondrial K(ATP) channel; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I; D003981:Diazoxide; D015655:1-Methyl-4-phenylpyridinium