Signs of alterations in the mitochondrial dynamic and oxidative stress in the senescence process during the development of estrogen-induced pituitary tumors

EZEQUIEL GRONDONA; MARIA EUGENIA SABATINO; MONGI BRAGATO BETHANIA; LUCÍA CARREÑO; LILIANA DEL VALLE SOSA; ALEXANDRA LATINI; ALICIA TORRES; ANA L DE PAUL

Mar del Plata

Congreso; LVI Reunión de la Sociedad Argenina de Investigación Clínica SAIC; 2016

Evidence of cellular senescence process during in vivo estrogen-inducedpituitary tumor development was recently describedin our laboratory. Since mitochondrial metabolism and dynamicare targets of estrogen action and senescence is considered astress response triggered by different factors including oxidativestress; we evaluate the effects of estrogen in vivo on mitochondrialfunction and dynamics in experimentallyinduced proliferative lesions. To induce pituitary tumoral development,Wistar male rats were exposed to estradiol benzoate(30mg) implanted subcutaneously in silastic capsules for 10, 20, 40and 60 days (E10-60). Control group: animals treated with emptycapsules. The morphological and morphometric mitochondrialanalysis was evaluated by transmission electron microscopy; ROSproduction and mitochondrial membrane potential was determinedby flow cytometry. Mfn1, Mfn2, OPA-1, Drp1; 8OHdG and Nrf2protein expression were assessed by immunohistochemistry andwestern blot. Statistical analysis: ANOVA-Fischer test (p <0.05).Increases in mitochondrial number accompanied by a circular andless elongated morphology was observed at E10. The gradual increaseof mitochondrial fusion proteins expression: Mfn1, Mfn2 andOPA-1 and the reduction of Drp1 fission protein levels, suggestedthe prevalence toward the mitochondrial fusion. A significant increasein ROS production and changes in mitochondrial membranepolarity, were signs of oxidative stress. The increase of nuclear8OHdG expression at the beginning of tumoral development andincreases in Nrf2 levels revealed the activation of defense mechanismsagainst the estrogen-induced proliferative injury. These datasuggest that alterations in the mitochondrial dynamic and oxidativestress detected in early stages of estrogen-induced pituitary tumordevelopment could be responsible for the emergence of senescenceas a regulatory mechanism of cellular growth.