Astroglia and steroid hormones such as estrogen and progesterone regulate cell growth, function, and protection in the central nervous system (CNS). It appears that astrocytes and steroids act in concert to promote cell survival under pathological conditions. With respect to the role of mitochondrial fusion and fission in energy metabolism, apoptosis, and proliferation, astrocyte mitochondria resemble a perfect intracellular target for steroids to modulate these processes, thereby promoting cell vitality after damage. We have studied the effects of estrogen and progesterone on cell viability in comparison with mitochondrial fusion and fission gene transcription in primary cortical astrocytes from female and male mouse brains. Estrogen-and progesterone-treated female astrocytes demonstrated an increase in cell number and proliferation marker accompanied by an upregulation of fusion and fission gene transcription, which were apparently balancing pro-and anti-apoptotic processes. On the other hand, male astrocytes exhibited no change in cell number after estrogen treatment, but a decrease after progesterone administration. This could be the consequence of stimulated apoptosis in male astrocytes by both steroids, which was counterbalanced by an increased proliferation in the presence of estrogen, whereas it was strengthened in the presence of progesterone. Supportively, estrogen promoted and progesterone decreased the transcription of fusion and fission genes. We suggest that estrogen and progesterone affect mitochondrial fusion and fission gene transcription in cortical astrocytes in a gender-specific way, thereby influencing mitochondrial function differently in both genders. Thus, interaction of sex steroids with mitochondria may represent one possible cause for gender differences in cellular pathology in the CNS.

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.

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