Estrogen suppresses brain mitochondrial oxidative stress in female and male rats

Abstract

Mitochondria are a major source of reactive oxygen species (ROS) and oxidative stress, key contributors to aging and neurodegenerative disorders. We report that gonadal hormones influence brain mitochondrial ROS production in both females and males. Initial experiments showed that estrogen decreases mitochondrial superoxide production in a receptor-mediated manner, as measured by MitoSOX fluorescence in differentiated PC-12 cells. We then assessed in vivo effects of gonadal hormones on brain mitochondrial oxidative stress in female and male rats. Brain mitochondria were isolated to measure a functional indicator of ROS, i.e., activity of the ROS-sensitive mitochondrial enzyme, aconitase. Gonadectomy of both males and females caused a decrease in aconitase activity, suggesting endogenous gonadal hormones influence mitochondrial ROS production in the brain. In vivo treatment of gonadectomized animals with testosterone or dihydrotestosterone (DHT) had no effect, but estrogen replacement significantly increased aconitase activity in brain mitochondria from both female and male rats. This indicates estrogen decreases brain mitochondrial ROS production in vivo. Sex hormone treatments did not affect protein levels of brain mitochondrial uncoupling proteins (UCP-2, 4, and 5). However, estrogen did increase the activity, but not the levels, of manganese superoxide dismutase (MnSOD), the mitochondrial enzyme that catalyzes superoxide radical breakdown, in brain mitochondria from both female and male rats. Thus, in contrast to the lack of effect of androgens on mitochondrial ROS, estrogen suppression of mitochondrial oxidative stress may influence neurological disease incidence and progression in both females and males.

Possible APOE Genotype and Sex Dependent Effects of 17-α- estradiol on Alzheimers Disease Pathology

“…β-E2 is also effective in several neural injury and toxicity models. In animal models of AD, β-E2 reduces Aβ pathology and improves cognition [15], although the effectiveness of β-E2 is reduced in the presence of APOE4 [16]. This latter observation is consistent with a role for APOE in modulating the biological effects of estrogen-based therapy.…”

Age-related changes in the activity and expression of manganese superoxide dismutase, and mitochondrial oxidant generation in female and male rats

“…It has been reported that in aged rats, female brain is less prone to oxidative damage than male brain [33]. Furthermore, estrogen treatment enhanced MnSOD activity whereas it had no effect on enzyme protein in brain mitochondria of female rats [35]. This study suggests that the expression and activity of MnSOD may not be well-correlated, and some factors may independently influence MnSOD activity.…”

“…Accordingly, the previous studies carried out in rats have reported that females had lower oxidative stress and mitochondrial dysfunction than the males [29][30][31]. However, these reports concerning the gender differences in mitochondrial oxidant status have either dealt with the 4-6 months old animals [32][33], or applied some interventions such as ovariectomy and estrogen replacement therapy [30,32,34,35].…”

Association of superoxide dismutases and NAD(P)H quinone oxidoreductases with prognosis of patients with breast carcinomas

“…32 SOD2 function can be modulated by estrogen and TP53, and thus it may be highly relevant for breast cancer progression and treatment. 33,34 Patients with the high activity Ala allele in SOD2 rs4880 SNP treated by cyclophosphamide had poorer breast cancer survival than patients with the low activity genotype Val/Val. 19,20 In our study, SOD2 rs4880 SNP did not significantly modify the PFS of patients treated by cyclophosphamide (n ¼ 89).…”