Antioxidant, Bioenergetic, and Metabolic Effects of Novel Mitochondria-Targeted Estrogens

Estrogens are steroid hormones that regulate antioxidant and mitochondrial bioenergetic metabolism in addition to activating nuclear genomic pathways. Concentrating these effects within the mitochondria is a novel strategy for ameliorating mitochondrial dysfunction, which is characteristic of cancer, metabolic, and neurodegenerative diseases. The use of synthetic mitochondria-targeted estrogens containing a triphenylphosphonium group may provide a basis for improving mitochondrial function in these conditions. Here, we evaluate the effects of two compounds, one derived from 17β-estradiol (mitoE2) and the other from 17α-ethinylestradiol (mitoEE2) on cell viability in MCF-7 and CCD-1112Sk cells. We further examine their influence on the activities of superoxide dismutase (MnSOD), citrate synthase (CS), cytochrome c oxidase (COX), and ATP synthase, as well as in the glycolytic reserve and cellular respiration. In both cellular models, cell viability assays indicated that MitoE2 was well tolerated below 500 nM, while MitoEE2 allowed treatments up to 100 nM for up to 24 hours. We found that the molecules act differently on enzymatic targets. Exposure of MCF-7 cells to mitoE2 resulted in reduced MnSOD activity. Pretreatment with MitoE2 or MitoEE2 restored the viability of MCF-7 cells exposed to H 2 O 2 -induced oxidative damage to levels comparable to untreated controls. Additionally, MitoEE2 increased the activities of CS and COX. Both mitochondria-targeted estrogens increased glycolytic reserve and mitochondrial respiration, as determined by extracellular flux assays. Overall, these findings suggest that the antioxidant and bioenergetic effects observed encourage further investigation into their potential as therapeutic strategies for conditions linked to mitochondrial dysfunction.