Acute energy deprivation in isolated neurons and tumor stem cells. Effects on intracellular calcium and mitochondrial function

Acute brain hypoxia/ischemia can occur in all parts of life e.g. during birth, trauma or disease, of which stroke is the most common cause. Neuroprotective measures are yet sparse. Tolerance to energy deprivation due to hypoxia or ischemia would be of great value in the acutely diseased brain. Such tolerance is limited in the adult human brain, which is the usual victim of stroke. Conversely in neonatal individuals such tolerance has been seen, as well as in malignant tissue where hypoxia tolerance is associated with therapy resistance. Loss of cellular calcium homeostasis and mitochondrial depolarization are key events leading to cell death. The aim of this thesis was to investigate the state of intracellular calcium and mitochondrial function after the onset of acute ischemia/hypoxia in neurons of the neonate and adult brain, and in patient-derived glioblastoma stem cells (GSCs) and their differentiated progeny. The results suggest that the sarcoplasmic/endoplasmic calcium ATPase (SERCA) is important in ischemic calcium deregulation. In addition, hypoxia was more deleterious to mitochondria than glutamate overload and glucose deprivation. Mitochondrial function was better preserved in neonatal neurons than in adults when exposed to acute hypoxia and reoxygenation. GSCs were surprisingly sensitive to hypoxia. However, short-term differentiation improved hypoxia tolerance. In conclusion oxygen dependency changes with development both in neurons and in tumor stem cells. Acquired hypoxia tolerance during stimulated differentiation in GSCs demonstrates a plasticity that brings hope to the idea of inducing hypoxia tolerance in the human brain