Download METABOLIC-REDOX ADAPTATIONS OF NEURONS AND

METABOLIC-REDOX ADAPTATIONS OF NEURONS AND ASTROCYTES TO
NEUROTRANSMISSION
Daniel Jimenez-Blasco1, Angel Herrero-Mendez1, Angeles Almeida1,2 and Juan P. Bolaños1
1
Institute of Functional Biology and Genomics (IBFG), University of Salamanca-CSIC,
Salamanca, Spain; 2Hospital Universitario de Salamanca, Instituto de Investigación
Biomedica de Salamanca (IBSAL), Salamanca, Spain
Email of the presenting author: [email protected]
Energy and redox conservation in the brain requires metabolic cooperation between distinct
cell types. We have identified mechanisms and factors that maintain cell specific programs to
allow this metabolic-redox collaboration. Neurons show a high dependence on mitochondrial
oxidative metabolism for survival, whereas astrocytes resist to almost complete inhibition of
mitochondrial respiration. A key factor in this process is PFKFB3 (6-phosphofructo-2kinase/fructose-2,6-bisphosphatase-3), an enzyme that promotes glycolysis by activating its
regulatory enzyme PFK1 (6-phosphofructo-1-kinase). We demonstrated that PFKFB3 is a
substrate of the E3 ubiquitin ligase, anaphase-promoting complex/cyclosome (APC/C)-Cdh1
(1). By regulating PFKFB3 protein stability, APC/C-Cdh1 controls the glycolysis versus
pentose-phosphate pathway (PPP) switch, redox status, and survival of neurons. During
glutamatergic neurotransmission, (APC/C)-Cdh1 is inhibited leading to PFKFB3 stabilization,
glycolysis activation and PPP inhibition in neurons. This unavoidably leads to oxidative
stress, since the intrinsic antioxidant defense of neurons is weak. However, the mechanism
whereby these cells are physiologically protected against oxidative damage during
glutamatergic neurotransmission is unknown. We have found that the antioxidant defense of
neurons is repressed owing to continuous protein destabilization of the master antioxidant
transcriptional activator, Nrf2 (2). By contrast, Nrf2 is highly stable in neighbor astrocytes
explaining their robust antioxidant defense and resistance against oxidative stress. 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 astrocyte NMDAR couples glutamatergic neurotransmission with
neuronal survival.
References
1. Herrero-Mendez et al. (2009) Nat. Cell Biol. 11:747-752.
2. Jimenez-Blasco et al. (2015) Cell Death Differ. 22:1877-1289.