Translational Research and Advanced Imaging Laboratory 

Invited Professor Juan P. Bolanos will give 3 lectures

Professeur Juan P. Bolanos (Salamanque University) is invited by the RMSB and by IdEx Bordeaux for a six months stay in Bordeaux; he will give 3 lectures (19/02, 16/04, 28/05)...

1/ Molecular bases of the metabolic programs of neurons and astrocytes 19 FEVRIER, 11H, PGF Energy and redox conservation in the brain requires metabolic cooperation between distinct cell types. We have identified mechanisms and factors that maintain cell-specific metabolic programs to allow this metabolic collaboration. Neurons show a high dependence on mitochondrial oxidative metabolism for survival, whereas astrocytes resist to almost complete inhibition of mitochondrial respiration. This is due to the up-regulation, in astrocytes but not in neurons, of glycolysis that generates ATP to maintain the mitochondrial membrane potential reverse ATPase activity. A key metabolic step in this process is PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3), an enzyme that promotes glycolysis by activating its regulatory enzyme PFK1 (6-phosphofructo-1-kinase). We showed that PFKFB3 is a substrate of the E3 ubiquitine ligase, anaphase-promoting complex/cyclosome (APC/C)-Cdh1. By regulating PFKFB3 protein stability, APC/C-Cdh1 activity controls the metabolic program, redox status, and survival of neurons and astrocytes. 

2/ Astrocytes boost neuronal protection during glutamatergic neurotransmission 16 APRIL, 11H, PGF Neurotransmission unavoidably increases mitochondrial reactive oxygen species. However, the intrinsic antioxidant defense of neurons is weak, hence the mechanism whereby these cells are physiologically protected against oxidative damage is unknown. We have found that the antioxidant defense of neurons is repressed due to continuous protein destabilization of the master antioxidant transcriptional activator, nuclear factor-erythroid 2-related factor-2 (Nrf2). By contrast, Nrf2 is highly stable in neighbor astrocytes explaining their robust antioxidant defense and resistance against oxidative stress. We also show that subtle and persistent stimulation of N-methyl-D-aspartate receptors (NMDAR) in astrocytes up-regulates a signal transduction pathway involving p35/Cdk5-mediated Nrf2 phosphorylation and activation, boosting antioxidant protection of closely spaced neurons. Thus, intercellular communication through NMDAR couples neurotransmission with neuronal survival.  

3/ Mitochondrial respiratory chain assembly dictates differential ROS production in neurons and astrocytes 28 MAY, 11H, PGF To understand the physiological roles of reactive oxygen species (ROS) in the brain, we studied the abilities of neuronal and astrocytic mitochondria to spontaneously form ROS. We found that ROS abundance is ~one order of magnitude higher in astrocytes than in neurons, which is an unexpected observation in view that astrocytes express high levels of antioxidants. Whilst the main source of ROS in both cell types is the mitochondrial electron transport chain, these differences cannot be ascribed to the distinct abundances of total complex I –a major source of mitochondrial superoxide anion. In contrast, we found that in astrocytes a large proportion of complex I protein occurs free, whereas in neurons most complex I is assembled within electron transport chain supercomplexes. Furthermore, we show that complex I assembly into supercomplexes regulates the production of mitochondrial ROS in neurons and astrocytes. This suggests a cell-specific physiological role for mitochondrial ROS in brain cells.

Dernière mise à jour mercredi 29 avril 2015