Steroid hormone effects on the mitochondrial morphology and physiology of primary astrocytes : implications for neuroprotection
Year: 2012
Type: dissertation
Abstract: Several points of interest in the neuroprotection field are approached in this work: steroid hormones, astrocytes and mitochondria. Steroid hormones, such as estrogen and progesterone, are well-known to regulate cell growth, function and protection in the central nervous system (CNS). Astrocytes play a major role in the brain's energy metabolism, growth, regulation of cerebral blood flow, coupling neuronal activity and regulation of synapses, as well as neuroprotection. Furthermore, the essential cellular energy metabolism, regulation of cell growth, division, signaling and also of apoptosis, is dependent on the mitochondrial functions. This explains why mitochondrial dysfunction can cause important cellular imbalance and is connected to aging and disease, including many neurodegenerative infirmities. Interestingly, the cell functions managed by mitochondria are also modulated by steroid hormones, so that it seems mitochondria are perfect targets for strategies of cellular protection. In the first part of this thesis, focus is put on the energy metabolism regulation in the CNS. Steroid hormones are well-known to fulfill a protective role in the brain during ischemic and degenerative processes. Mitochondrial dysfunctions due to abnormalities of the mitochondrial respiratory chain often accompany neurodegenerative diseases, in which, degeneration often shows brain region specificity. Since astrocytes function as the major energy supplier in the CNS, the estrogen effects on the mitochondrial respiratory chain were here analyzed in primary astrocytes from the brain regions cortex and mesencephalon. It was observed that estrogen influences subunit gene expression of respiratory chain complexes, the mitochondrial DNA content and the functional respiration of isolated mitochondria differently, according to the estrogen exposure time as well as depending on the brain region. This could be related to the different sensitivity of brain regions to degeneration and also point at an important indirect mechanism by which estrogen protects neurons from cell death under neurotoxic conditions. On a subsequent chapter, the processes of mitochondrial fusion and fission that regulate energy metabolism, apoptosis, and cell proliferation, were approached. In this respect, astrocyte mitochondria seem to be a perfect intracellular target for steroids to modulate these processes. Therefore, 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 are studied here. Estrogen- and progesterone-treated astrocytes demonstrated differences in cell number and proliferation marker accompanied by a corresponding difference of fusion and fission gene transcription, in a gender-dependent way. It seems estrogen and progesterone affect mitochondrial function differently in both genders. Therefore, interaction of sex steroids with mitochondria may represent one possible cause for gender differences in cellular pathology in the CNS. The last part of this thesis focuses on mitochondrial fusion and fission processes during mouse brain development. Mitochondria are responsible for major cellular functions, therefore playing a central role in tissue development and maintenance as well as in senescence and disease. The complex and dynamic processes of mitochondrial fusion and fission regulate the maintenance of the mitochondrial network. When imbalanced, they cause deep changes in mitochondrial architecture and consequently on their function. Steroid hormones, as progesterone and estrogen, influence brain development and neuroprotection directly and indirectly through their action on the neuroprotective astrocytes. These studies aim at understanding the effects steroid hormones have on the fission and fusion events in mitochondria and what contribution this might play in brain development, tissue-specialization mechanisms and astrocyte survival, influencing neuroprotection. Therefore , the mRNA levels of the target fusion and fission genes were measured during mouse brain cortex development. The results correlate very well with the previous published work by others, on the stages of cell growth and specializations during mice cortex development, and have shown some sex-specific differences.
Source: RWTH Publications (RWTH Aachen)
Author: de Castro Lopo Wright de Araujo, Gilda Catarina
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7043635327