Reduced 17β-estradiol following ovariectomy induces mitochondrial dysfunction and degradation of synaptic proteins in the entorhinal cortex

Reductions in circulating estrogens can contribute to cognitive decline, in part by impairing mitochondrial function within the hippocampal region. The entorhinal cortex provides the hippocampus with its main cortical inputs. To assess the impact of estrogen deficiency on mitochondrial respiration and synaptic proteins in the entorhinal cortex, female wildtype rats received either sham surgery, bilateral ovariectomy, or ovariectomy with implantation of a subdermal capsule to maintain low levels of circulating 17 beta-estradiol (E2). Mitochondrial respiration in the entorhinal cortex was not significantly affected two weeks following ovariectomy, but there was a reduction in oxygen consumption four weeks after ovariectomy that was prevented by E2 supplementation. The expression of mitochondrial membrane integrity element voltage-dependent anion channel protein (VDAC1) was also reduced four weeks after ovariectomy, suggesting that respiration was reduced due to a decline in mitochondrial density. Ovariectomy also increased mitochondrial and cytoplasmic cytochrome c and upregulated superoxide dismutase 2 (SOD2) both two and four weeks after ovariectomy, reflecting mitochondrial electron leakage and oxidative redox imbalance. Further, the ovariectomy-induced changes in mitochondrial proteins were associated with reductions in postsynaptic density protein 95 (PSD95) and the presynaptic protein synaptophysin. There were no changes in mitochondrial or synaptic proteins in ovariectomized animals that received E2 supplementation. Our findings indicate that reductions in circulating 17 beta-estradiol induced by ovariectomy disrupt mitochondrial functions in the entorhinal cortex, and suggest that a resulting increase in oxidative stress contributes to the degradation in synaptic proteins that may affect cognitive functions mediated by the hippocampal region.