Abstract
The neuroprotective effect of mitochondrial isocitrate dehydrogenase (IDPm), an enzyme involved in the reduction of NADP+ to NADPH and the supply of glutathione (GSH) in mitochondria, was examined using SH-SY5Y cells overexpressing IDPm (S1). S1 cells showed higher NADPH and GSH levels than vector transfectant (V) cells and were more resistant to staurosporine-induced cell death than controls. Staurosporine-induced cytochrome c release, caspase-3 activation, and production of reactive oxygen species (ROS) were significantly attenuated in S1 cells as compared to V cells and reduced by anti-oxidants, trolox and GSH-ethyl ester (GSH-EE). Staurosporine-induced the release of Mcl-1 from mitochondria that formed a complex with Bim. Mcl-1 was then cleaved to a shortened form in a caspase-3 dependent manner; its release was attenuated far more in S1 than in V cells after staurosporine treatment. Finally, the staurosporine-induced decrease in mitochondrial membrane potential (Δψm) was correlated with the time of mitochondrial Mcl-1 release; the loss of Δψm was attenuated significantly in S1 cells as compared to that in V cells. These results suggest that the neuroprotective effect of IDPm may result from increases in NADPH and GSH levels in the mitochondria. This, in turn, inhibits mitochondrial ROS production after cytochrome c release, which seems to be mediated through Mcl-1 release.
| Original language | English |
|---|---|
| Pages (from-to) | 139-152 |
| Number of pages | 14 |
| Journal | Journal of Neuroscience Research |
| Volume | 85 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2007 Jan 1 |
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All Science Journal Classification (ASJC) codes
- Cellular and Molecular Neuroscience
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Mitochondrial isocitrate dehydrogenase protects human neuroblastoma SH-SY5Y cells against oxidative stress. / Kim, Sun J.; Yune, Tae Y.; Han, Ching T.; Kim, Young C.; Oh, Young J.; Markelonis, George J.; Oh, Tae H.
In: Journal of Neuroscience Research, Vol. 85, No. 1, 01.01.2007, p. 139-152.Research output: Contribution to journal › Article
TY - JOUR
T1 - Mitochondrial isocitrate dehydrogenase protects human neuroblastoma SH-SY5Y cells against oxidative stress
AU - Kim, Sun J.
AU - Yune, Tae Y.
AU - Han, Ching T.
AU - Kim, Young C.
AU - Oh, Young J.
AU - Markelonis, George J.
AU - Oh, Tae H.
PY - 2007/1/1
Y1 - 2007/1/1
N2 - The neuroprotective effect of mitochondrial isocitrate dehydrogenase (IDPm), an enzyme involved in the reduction of NADP+ to NADPH and the supply of glutathione (GSH) in mitochondria, was examined using SH-SY5Y cells overexpressing IDPm (S1). S1 cells showed higher NADPH and GSH levels than vector transfectant (V) cells and were more resistant to staurosporine-induced cell death than controls. Staurosporine-induced cytochrome c release, caspase-3 activation, and production of reactive oxygen species (ROS) were significantly attenuated in S1 cells as compared to V cells and reduced by anti-oxidants, trolox and GSH-ethyl ester (GSH-EE). Staurosporine-induced the release of Mcl-1 from mitochondria that formed a complex with Bim. Mcl-1 was then cleaved to a shortened form in a caspase-3 dependent manner; its release was attenuated far more in S1 than in V cells after staurosporine treatment. Finally, the staurosporine-induced decrease in mitochondrial membrane potential (Δψm) was correlated with the time of mitochondrial Mcl-1 release; the loss of Δψm was attenuated significantly in S1 cells as compared to that in V cells. These results suggest that the neuroprotective effect of IDPm may result from increases in NADPH and GSH levels in the mitochondria. This, in turn, inhibits mitochondrial ROS production after cytochrome c release, which seems to be mediated through Mcl-1 release.
AB - The neuroprotective effect of mitochondrial isocitrate dehydrogenase (IDPm), an enzyme involved in the reduction of NADP+ to NADPH and the supply of glutathione (GSH) in mitochondria, was examined using SH-SY5Y cells overexpressing IDPm (S1). S1 cells showed higher NADPH and GSH levels than vector transfectant (V) cells and were more resistant to staurosporine-induced cell death than controls. Staurosporine-induced cytochrome c release, caspase-3 activation, and production of reactive oxygen species (ROS) were significantly attenuated in S1 cells as compared to V cells and reduced by anti-oxidants, trolox and GSH-ethyl ester (GSH-EE). Staurosporine-induced the release of Mcl-1 from mitochondria that formed a complex with Bim. Mcl-1 was then cleaved to a shortened form in a caspase-3 dependent manner; its release was attenuated far more in S1 than in V cells after staurosporine treatment. Finally, the staurosporine-induced decrease in mitochondrial membrane potential (Δψm) was correlated with the time of mitochondrial Mcl-1 release; the loss of Δψm was attenuated significantly in S1 cells as compared to that in V cells. These results suggest that the neuroprotective effect of IDPm may result from increases in NADPH and GSH levels in the mitochondria. This, in turn, inhibits mitochondrial ROS production after cytochrome c release, which seems to be mediated through Mcl-1 release.
UR - http://www.scopus.com/inward/record.url?scp=33846180328&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33846180328&partnerID=8YFLogxK
U2 - 10.1002/jnr.21106
DO - 10.1002/jnr.21106
M3 - Article
C2 - 17075901
AN - SCOPUS:33846180328
VL - 85
SP - 139
EP - 152
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research
SN - 0360-4012
IS - 1
ER -