Estradiol protects against ATP depletion, mitochondrial membrane potentialdecline and the generation of reactive oxygen species induced by 3-nitroproprionic acid in SK-N-SH human neuroblastoma cells

Mitochondria are recognized as modulators of neuronal viability during isch emia, hypoxia and toxic chemical exposure, wherein mitochondria dysfunction leading to ATP depletion may be a common pathway of cell death. Estrogens have been reported to be neuroprotective and proposed to play a role in the modulation of cerebral energy/glucose metabolism. To address the involveme nt of 17 beta -estradiol preservation of mitochondrial function, we examine d various markers of mitochondrial activity in human SK-N-SH neuroblastoma cells exposed to 3-nitroproprionic acid (3-NPA), a succinate dehydrogenase inhibitor which uncouples oxidative phosphorylation. 3-NPA (10 mM) signific antly increased ATP levels at 2 h then caused a 40% and a 50% decrease in A TP levels from baseline when treated for 12 h and 24 h, respectively. 3-NPA also induced significant increases in levels of cellular hydrogen peroxide and peroxynitrite at 2 h and a 60% decrease in mitochondrial membrane pote ntial (MMP) at 12 h exposure. 17 beta -Estradiol (17-betaE(2)) pretreatment restored the ATP level back to 80% at 12 h of that in control cells treate d with 3-NPA but without E-2, blunted the effect of 3-NPA on MMP and reacti ve oxygen species levels. The present study indicates that 17 beta -E-2 can preserve mitochondrial function in the face of inhibition of oxidative pho sphorylation.