Short talk:
Recent uncovered protective strategies in neurons against lipotoxicity in brain, an organ with very high fat content, rapid ATP turnover and large oxygen consumption

Georg Reiser1, Peter Schönfeld2

1Medizinische Fakultät, Otto-von-Guericke-Universität Magdeburg, Institut für Inflammation und Neurodegeneration (Neurobiochemie), , Magdeburg, Germany, 2Medizinische Fakultät, Otto-von- Guericke-Universität Magdeburg, Institut für Biochemie und Zellbiologie, Magdeburg, Germany

Human brain has 60% fat / dry weight. It is thus an organ with one of the highest body fat content. This high amount is explained by the large degree of membranal lipids required for brain’s functional integrity. But, due to inherent properties, neurons have very high ATP demand, and consequently a high oxygen consumption. However, free fatty acids (FFA) exert deleterious activities on mitochondrial conversion of redox energy into ATP (see refs. in [Schönfeld P, Reiser G, 2013, Why does brain metabolism not favour burning of fatty acids to provide energy? . J. Cerebral Blood Flows & Metabolism 33, 1493-1499]). In addition, FFA stimulate mitochondria to production of reactive oxygen species (ROS), either as hydrogen delivering substrates or by partial electron transport block within the respiratory chain. Due to their poor antioxidative equipment, neurons respond particularly sensitive to FA-linked ROS generation. Several processes enhance cerebral FFA levels, such as uptake of FFA from circulation into brain tissue or increased hydrolytic degradation of membrane phospholipids in traumatic or hypoxic brain injuries. We propose the following main strategies to protect neurons against FFA-linked lipotoxicity: 1) spurning β-oxidation in mitochondria of neurons. 2) the supply from astrocytes of relevant metabolites to neurons for antioxidants synthesis. 3) neural autophagy of ROS-emitting mitochondria combined with transfer of degradation-committed FFA for disposal in astrocytes. This is an eminently potent protective strategy against ROS and harmful FFA activities. 4) estrogens and, generally, neurosteroids as protective triggers via ERK- and PKB-mediated signaling to initiate expression of neuronal survival genes via CREB.


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