JoX, Vol. 15, Pages 170: Estrogen Degradation Metabolites: Some Effects on Heart Mitochondria

Journal of Xenobiotics doi: 10.3390/jox15050170

Authors:
Cristina Uribe-Alvarez
Elizabeth Lira-Silva
Lilia Morales-García
Natalia Chiquete-Felix
Francisco Javier Roldán-Gómez
Jesús Vargas-Barrón
José J. García-Trejo
Alejandro Silva-Palacios
Salvador Uribe-Carvajal
Natalia Pavón

Mitochondria play crucial roles in various cellular functions, including ATP production, apoptosis, and calcium homeostasis. Signaling pathways and hormones such as estrogens regulate the mitochondrial network through genetic, epigenetic, and metabolic processes. Estrogens increase the efficiency of mitochondrial oxidative phosphorylation by preventing uncoupling. Upon reaching menopause, when estrogen levels decrease, impaired mitochondrial function (uncoupled oxidative phosphorylation, lower ATP yields) is observed. Like all hormones in the body, estrogens undergo metabolic processing, resulting in estrogenic degradation metabolites (EDMs). These metabolites can form adducts with genomic and mitochondrial DNA and are of particular interest due to their potential role as carcinogens. Given that estradiol influences mitochondrial function, it is possible that EDMs may have an impact on heart mitochondria. To investigate this, we used isolated heart mitochondria from control and oophorectomized (mimicking menopausal stage) female Wistar rats of the same age. We found that mitochondria exposed to EDMs exhibited reduced coupling of oxidative phosphorylation and diminished ATP production, while increasing reactive oxygen species generation. Furthermore, these effects were significantly stronger in mitochondria from oophorectomized rats than in mitochondria from control (intact) rats. In addition, mitochondrial oxidative phosphorylation complex activities were differentially affected: complex I and ATPase activities decreased, while complex IV remained unaffected. We propose that exposure to EDMs promotes mitochondrial dysfunction in rats and that these effects are exacerbated by oophorectomy, a procedure commonly used to model the effects of menopause in women.

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