Effect of estrogens on base excision repair in brain and liver mitochondria of aged female rats
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RESEARCH ARTICLE
Effect of estrogens on base excision repair in brain and liver mitochondria of aged female rats R. Lecle`re • R. Torregrosa-Mun˜umer R. Kireev • C. Garcı´a • E. Vara • J. A. F. Tresguerres • R. Gredilla
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Received: 25 February 2013 / Accepted: 2 May 2013 / Published online: 12 May 2013 Ó Springer Science+Business Media Dordrecht 2013
Abstract Changes in the endocrine system have been suggested to act as signaling factors in the regulation of age-related events. Among the different hormones that have been linked to the aging process, estrogens have been widely investigated. They have been associated with inflammatory and oxidative processes and several investigations have established a relationship between the protective effects of estrogens and the mitochondrial function. Mitochondrial DNA is subjected to continuous oxidative attack by free radicals, and the base excision repair (BER) pathway is the main DNA repair route present in mitochondria. We have investigated the effect of estrogen levels on some of the key enzymes of BER in brain and liver mitochondria. In both tissues, depletion of estrogens led to an increased mitochondrial AP endonuclease (mtAPE1) activity, while restoration of estrogen levels by exogenous supplementation resulted in restitution of control APE1 R. Lecle`re and R. Torregrosa-Mun˜umer contributed equally to this study. R. Lecle`re R. Torregrosa-Mun˜umer R. Kireev J. A. F. Tresguerres R. Gredilla (&) Department of Physiology, Faculty of Medicine, Complutense University, Plaza Ramon y Cajal s/n, 28040 Madrid, Spain e-mail: [email protected] C. Garcı´a E. Vara Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, Madrid, Spain
activity only in liver. Moreover, in hepatic mitochondria, changes in estrogen levels affected the processing of oxidative lesions but not deaminations. Our results suggest that changes in mtAPE1 activity are related to specific translocation of the enzyme from the cytosol into the mitochondria probably due to oxidative stress changes as a consequence of changes in estrogen levels. Keywords Mitochondria Estrogens DNA Base excision repair AP endonuclease Aging
Introduction Brain and liver play a central role in the aging process. While brain is critical due to its major role in homeostasis of the organism, liver plays a central role in metabolic control of nutrients and xenobiotics. Both suffer morphological and functional modifications during aging. Brain aging is characterized by both cognitive and behavioral declines. Decrease in dendritic spine densities (Dickstein et al. 2007), alterations in signaling pathways (Dro¨ge and Schipper 2007; Foster 2007) and neurotransmitter systems (Mora et al. 2007) occur with normal aging, favoring general neuronal dysfunction. Moreover, a reduction in the number of neurons in the hilus of the dentate gyrus, together with a very noticeable reduction in BrDU positive cells, a marker of neurogenesis, have also been described with age (Azcoitia et al. 2
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