Bioenergetics and Oxidative Stress in the Nervous System
Our laboratory is interested in understanding the molecular mechanisms that regulate the energetic and redox homeostasis in the cells of the central nervous system. In particular, we are studying the proteins and signaling pathways responsible for the adaptation of the neuronal metabolism to the continuous and high energetic and antioxidant demand imposed by neurotransmission.
We have observed that, in spite of the enormous energy demand that the neurotransmission process requires, neurons only scarcely utilize glucose as metabolic fuel –in contrast to the vast majority of cells. This is due to the absence –by ubiquitylation and proteasomal degradation– of just one enzyme, PFKFB3 (6-phosphofructo-2-kiinase/fructose-2,6-bisphosphatase-3) (Herrero-Mendez et al., 2009), which catalyzes the biosynthesis of fructose-2,6-bisphosphate (F26BP), a potent positive allosteric effector of 6-phosphofructo-1-kinase (PFK1). The glycolytic pathway is, therefore, inhibited in neurons, although glucose metabolism is shifted towards the pentose-phosphate pathway (Bolaños and Almeida, 2010). Thanks to this oxidative pathway, neurons conserve the redox energy of glucose as NADPH(H+), an essential cofactor in the regeneration of antioxidants, such as glutathione or thioredoxin (Quintana-Cabrera et al., 2012). Thus, by stabilizing PFKFB3, the glycolytic pathway is activated in neurons, although they suffer from oxidative stress, and they die (Rodriguez-Rodriguez et al., 2012). Therefore, in order to maintain their antioxidant homeostasis, neurons need to metabolically adapt and utilize alternative energetic fuels, which must be oxidized in the mitochondria (Fernandez-Fernandez et al., 2012). This would explain why mitochondrial metabolism in neurons most contributes to the high degree of brain oxygen consumption. Our group studies the molecular mechanisms responsible for the metabolic adaptation of neurons to this status, including proteins (and other factors) that i) regulate the energetic homeostasis, ii) regulate the antioxidant homeostasis, and iii) responsible for the adequate coordination of both processes.
We believe that, besides the advance in knowledge, the potential results of our research line would allow to identify specific metabolic targets, which genetic alterations contribute to neurotransmission malfunctioning and cause many neurological problems, including neurodegenerative diseases.
Bioenergetic and redox coupling between neurons and astrocytes Up-left: The glycolytic activity in neurons is very low when compared with astrocytes; PFKFB3 stabilization after Cdh1 inhibition (cofactor for the anaphase-promoting complex/cyclosome or APC/C) by RNA interference is sufficient to double neuronal glycolytic activity. Up-right: summary of the main metabolic fate of glucose in neurons, the pentose-phosphate pathway, reflecting the role that plays PFKFB3 protein stability in this process. Bottom: scheme that summarizes the notion that astrocytes contribute to the neurotransmission function of neurons through the elimination of neurotransmitters (glutamate) from the synaptic space, a phenomenon that is bioenergetically coupled in satisfying the energetic and antioxidant demand of neurons.
Miembros del grupo
|Juan Pedro Bolaños||Full Professor (USAL)|
|Emilio Fernández||Associate Professor (USAL)|
|Juan Pedro Bolaños||
| Lopez-Fabuel I, Le Douce J, Logan A, James AM, Bonvento G, Murphy MP, Almeida A and Bolaños JP (2016)
Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes
Proc. Natl. Acad. Sci. U.S.A. 113: 13063-13068
| Requejo-Aguilar R, Lopez-Fabuel I, Fernandez E, Martins LM, Almeida A and Bolaños JP (2014)
PINK1 deficiency sustains cell proliferation by re-programming glucose metabolism through HIF1
Nat. Commun. 5:4514
| Deuse T, Hua X, Wang D, Maegdefessel L, Heeren J, Scheja L, Bolaños JP, et al. and Schrepfer S (2014)
Dichloroacetate prevents restenosis in preclinical animal models of vessel injury
| Quintana-Cabrera R, Fernandez-Fernandez S, Bobo-Jimenez V, Garcia-Escobar J, Sastre J, Almeida A and Bolaños JP (2012)
γ-Glutamylcysteine detoxifies reactive oxygen species by acting as glutathione peroxidase-1 cofactor.
Nat. Commun. 3: 718
| Herrero-Mendez A, Almeida A, Fernandez E, Maestre C, Moncada S and Bolaños JP (2009)
The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1
Nat. Cell Biol. 11, 747-752
Proyectos de investigación