| dc.description.abstracteng | This work should address the question of whether mitochondrially-generated ROS are the possible cause of neuronal dysfunction in RTT. Data collected in previous studies suggest that oxidative stress is important for the disease progression. Since mitochondria, as "cell power plants", contribute significantly to the production of ROS, possible increased ROS levels in MeCP2-deficient neurons have also been sought under physiological stimulation. The results indicate that the mitochondria, due to their overall comparatively weak redox responses, are only partially responsible for ROS-induced cell stress in RTT.
By means of the fluorescent redox indicator roGFP1, the oxidation state of the mitochondria was reliably measured dynamically and semiquantitatively for the first time in RTT. The determined redox state and its change, after physiologically relevant stimulation, by the neurotransmitters glutamate, dopamine, serotonin and norepinephrine, shows the redox balance and the potentially limited functions of the cell.
It was impressively demonstrated that neurotransmitters have an influence on the redox state of the mitochondria. In general, it is striking that the oxidative events in mitochondria, with identical treatment and measurement protocols, are weaker than in the cytosol. This is due to several factors. First, the presence of a phospholipid double membrane surrounding the mitochondria creates an additional protective barrier. Double membranes are naturally highly impermeable to superoxide. However, H2O2 molecules that emerge from the SOD-catalyzed reaction are membrane-permeable. They can diffuse both into and out of the mitochondria. Since they can leave the actual place of origin of the superoxides, may be incorrect conclusions results. It is also assumed that the electrons escaping on their way through the electron transport chain of the complexes I-IV of the respiratory chain in the form of superoxides especially be released in the intermembrane space, consequently a low roGFP1m signal is detected. This gives the impression that ROS are produced less mitochondrially than cytosolic. It is possible that the proportion of ROS escaping into the intermembrane space is greater than assumed. Another reason for lower mitochondrial redox responses might be due to better formed mitochondrial redox buffering systems of the matrix, viz. a. Glutathione peroxidase, superoxide dismutase, peroxiredoxin III and catalase. In this regard, further, detailed investigations of mitochondrial redox homeostasis in WT neurons and MeCP2-deficient neurons would have to be carried out, and ideally also the intermembrane space would be included. | de |