Iptakalim ameliorates MPP+-induced astrocyte mitochondrial dysfunction by increasing mitochondrial complex activity besides opening mitoK(ATP) channels.
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.
Zhang
Shu
S
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, Peoples Republic of China.
Ding
Jian-Hua
JH
Zhou
Fang
F
Wang
Zhi-Yuan
ZY
Zhou
Xi-Qiao
XQ
Hu
Gang
G
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
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