Oestrogen Influences on Mitochondrial Gene Expression and Respiratory Chain Activity in Cortical and Mesencephalic Astrocytes

Abstract

The regulation of mitochondrial energy metabolism plays an essential role in the central nervous system (CNS). Abnormalities of the mitochondrial respiratory chain often accompany neurodegenerative diseases. This makes mitochondria a perfect target for strategies of cellular protection against toxic compounds and pathological conditions. Steroid hormones, such as oestrogen, are well-known to fulfil a protective role in the brain during ischaemic and degenerative processes. Because astrocytes function as the major energy supplier in the CNS, we have analysed oestrogen effects on the mitochondrial respiratory chain of this cell type. In our studies, we applied semi- and quantitative polymerase chain reaction analysis of gene expression and polarographic measurements of the respiratory chain activity of mitochondria. We observed that structural and functional properties were regulated dependent on the oestrogen exposure time and the brain region, but independent of the nuclear oestrogen receptors. We could demonstrate that long-term oestrogen exposure increases the subunit gene expression of respiratory chain complexes and the mitochondrial DNA content, thereby indicating an up-regulation of the amount of mitochondria per cell together with an increase of mitochondrial energy production. This could represent an important indirect mechanism by which long-term oestrogen exposure protects neurones from cell death under neurotoxic conditions. On the other hand, we observed short-term effects of oestrogen on the activity of mitochondrial, proton-pumping respiratory chain complexes. In astrocytes from the cortex, respiratory chain activity was decreased, whereas it was increased in astrocytes from the mesencephalon. An increased production of reactive oxygen species would be the consequence of an increased respiratory chain activity in mesencephalic astrocytes. This could explain the different efficiencies of oestrogen-mediated short-term protection in distinct brain regions, but also indicates the limitations for a therapeutic short-term application of oestrogen.

Gender-specific regulation of mitochondrial fusion and fission gene transcription and viability of cortical astrocytes by steroid hormones

“…In recent studies, we and others have shown that E promotes the expression of mitochondria-encoded subunits of the respiratory chain, thereby influencing mitochondrial respiratory activity and enhancing functional efficiency (Araú jo et al 2008, Irwin et al 2008. Mitochondrial functions are not only affected by regulation of nuclear and mitochondrial gene expression and activity of the respiratory chain (Zheng & Ramirez 1999, Araú jo et al 2008, Irwin et al 2008), but K7 M E or P for 24 h. Antagonists of estrogen and progesterone receptors (ICI and Rti respectively) were added simultaneously to the respective steroid hormone treatment. Specific quantification of fusion genes, Mfn1 (A and C; grey columns) and Mfn2 (A and C; black columns), and fission genes, Dnm1l (B and D; grey columns) and Fis1 (B and D; black columns), was performed by RT-PCR.…”

“…Cultured cortical astrocytes were treated with E concentrations known to be effective in the brain (Luconi et al 1999, Ivanova et al 2001, Pawlak et al 2005, von Schassen et al 2006, Araú jo et al 2008. Under basal (physiological) conditions, cultured cortical astrocytes from males and females did not differ in their characteristics for mitochondria morphology and cell viability.…”

Estrogen and the regulation of mitochondrial structure and function in the brain

“…In another project, we have investigated the influence on the transcription levels of mitochondrial DNA in cortical astrocytes and demonstrated that estrogen is capable of promoting transcriptional activity by approx. 50% [68]. Although there is still uncertainty of attributing these effects to direct estrogen-mitochondrion interactions, the chosen experimental approach in these experiments by using isolated mitochondria is in support for this view.…”

Regulation of mitochondrial respiratory chain biogenesis by estrogens/estrogen receptors and physiological, pathological and pharmacological implications

“…Consistent with the increased gene expression is the increased respiratory control ratio, elevated complex IV activity, in association with simultaneous reduction of free radical generation in brain. Araújo et al [117] examined E 2 effects on MRC gene expression and the MRC activity of rat cortical and mesencephalic astrocytes. They observed that MRC structural and functional properties were regulated dependent on the E 2 exposure time and the brain region, but independent of the nuclear ERs.…”