Mitochondrial isocitrate dehydrogenase protects human neuroblastoma SH-SY5Y cells against oxidative stress

✍ Scribed by Sun J. Kim; Tae Y. Yune; Ching T. Han; Young C. Kim; Young J. Oh; George J. Markelonis; Tae H. Oh

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 747 KB
• Volume: 85
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/jnr.21106

✦ Synopsis

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 antioxidants, 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 (Δψ~m~) was correlated with the time of mitochondrial Mcl‐1 release; the loss of Δψ~m~ 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. © 2006 Wiley‐Liss, Inc.