Protection against oxidant-induced apoptosis by mitochondrial thioredoxin in SH-SY5Y neuroblastoma cells.
Mitochondrial oxidative stress plays important roles in aging and age-related degenerative disorders. The newly identified mitochondrial thioredoxin (mtTrx; Trx2) is a key component of the mitochondrial antioxidant system which is responsible for the clearance of reactive intermediates and repairs proteins with oxidative damage. Here, we show that in cultured SH-SY5Y human neuroblastoma 1cells, overexpression of mtTrx inhibited apoptosis and loss of mitochondrial membrane potential induced by a chemical oxidant, tert-butylhydroperoxide (tBH). The effects of calcium ionophore (Br-A23187) were not affected by mtTrx, suggesting the protection was specific against oxidative injury. The mitochondrial glutathione pool was oxidized by tBH, and this oxidation was not inhibited by increased mtTrx. Consequently, the antioxidant function of mtTrx is not redundant, but rather in addition, to that of GSH. Mutations of Cys90 and Cys93 to serines rendered mtTrx ineffective in protection against tBH-induced cytoxicity. These data indicate that mtTrx controls the mitochondrial redox status independently of GSH and is a key component of the defensive mechanism against oxidative stress in cultured neuronal cells.
Chen
Yan
Y
The Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Yu
Min
M
Jones
Dean P
DP
Greenamyre
J Timothy
JT
Cai
Jiyang
J
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D000001:Calcimycin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016877:Oxidants / Q000633:toxicity*; D010084:Oxidation-Reduction; D013879:Thioredoxins / Q000378:metabolism*; D020122:tert-Butylhydroperoxide / Q000633:toxicity*
D000900:Anti-Bacterial Agents; D024101:Mitochondrial Proteins; D016877:Oxidants; C467002:TXN2 protein, human; D000001:Calcimycin; D013879:Thioredoxins; D020122:tert-Butylhydroperoxide; D005978:Glutathione