Superoxide anion regulates the mitochondrial free Ca2+ through uncoupling proteins.
Mitochondrial dysfunction, which is closely related to intracellular calcium overload and excessive free radicals, is an important cause of Alzheimer's disease (AD). However, molecular mechanisms of the mitochondrial Ca(2+) disregulation induced by oxidative stress in AD are still obscure. In an effort to gain a further understanding of this problem, we investigated the effects of superoxide anion, a primary free radical, on the expression of uncoupling proteins (UCPs) and the mitochondrial free Ca(2+) levels in the neuroblastoma SH-SY5Y cell line (neo) and stably expressed wild-type human APP(APP) and APP-Swedish mutation (APPsw) SH-SY5Y cells. It was found that UCP2 and UCP4 protein levels were upregulated in neo but downregulated in APP and APPsw cells by the superoxide anion. Our results show that the superoxide anion can regulate protein levels of UCP2 and UCP4 in SH-SY5Y cells, and the mitochondrial free Ca(2+) shifted their levels, tightly coupled with the protein levels of UCPs. When UCP2 and UCP4 were knocked down by siRNA, the result was reversed. These data suggest that the superoxide anion can regulate the mitochondrial free Ca(2+) by regulating the expression of UCPs. These observations also indicate that UCPs can be potential targets in pathotherapy prevention of AD.
State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, the P.R. China.
Zhaofei
Z
Wu
Jie
J
Zhang
Baolu
B
Zhao
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000838:Anions; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009154:Mutation; D047495:PPAR gamma / Q000502:physiology; D034741:RNA, Small Interfering; D013481:Superoxides / Q000378:metabolism*; D000071256:Uncoupling Protein 1
D016564:Amyloid beta-Protein Precursor; D000838:Anions; D017931:DNA Primers; D007473:Ion Channels; D024101:Mitochondrial Proteins; D047495:PPAR gamma; D034741:RNA, Small Interfering; D000071256:Uncoupling Protein 1; D013481:Superoxides; D002118:Calcium