Direct effects of corticosterone on ATP production by mitochondria from immortalized hypothalamic GT1-7 neurons.
Glucocorticoids are known to decrease intracellular ATP levels in the brain. This study was performed to investigate whether corticosterone at physiological levels depresses mitochondrial ATP production by directly acting on mitochondria. Mitochondria were isolated from immortalized hypothalamic GT1-7 neurons. ATP levels were determined using a luciferase-luciferin assay. When malate, alpha-ketoglutarate or pyruvate was used as a respiration substrate, corticosterone at > or =100 nM decreased ATP production by 10%. In contrast, corticosterone did not affect ATP production when succinate or N,N,N',N'-tetramethyl-p-phenylenediamine+ascorbate were used. To investigate the specificity of corticosterone inhibition, we examined several steroids. All steroids tested suppressed mitochondrial ATP production by 10% at a concentration of 100 nM, in a manner similar to that of corticosterone. To examine the effects of corticosterone on GT1-7 cell physiology, we incubated GT1-7 cells with t-butyl hydroperoxide (t-BuOOH) with corticosterone. Corticosterone largely enhanced t-BuOOH-induced cell death. These results indicate that corticosterone non-specifically inhibits mitochondrial ATP production by suppressing electron transfer from NADH to the electron transfer chain through complex I. Partial inhibition of mitochondrial ATP production by corticosterone may contribute to oxidative stress-induced cell death.
Fujita
Chisako
C
Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, Nakacho, Koganei, Tokyo 184-8588, Japan.
Ichikawa
Fumito
F
Teratani
Toshiaki
T
Murakami
Gen
G
Okada
Takahiro
T
Shinohara
Masaki
M
Kawato
Suguru
S
Ohta
Yoshihiro
Y
D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D003345:Corticosterone / Q000494:pharmacology*; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013256:Steroids / Q000494:pharmacology; D020122:tert-Butylhydroperoxide / Q000633:toxicity
D017382:Reactive Oxygen Species; D011965:Receptors, Glucocorticoid; D013256:Steroids; D000255:Adenosine Triphosphate; D020122:tert-Butylhydroperoxide; D003345:Corticosterone