Juan Pedro Bolaños

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 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 the 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, low in neurons, although glucose metabolism is shifted towards the pentose-phosphate pathway. 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. Thus, when by stabilizing PFKFB3 the glycolytic pathway becomes activated in neurons, these cells suffer from oxidative stress and eventually die. Therefore, in order to maintain their antioxidant homeostasis, neurons are metabolically adapted to utilize alternative energetic fuels, which must be oxidized in the mitochondria (Bolaños, 2016). 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 energy homeostasis, (ii) regulate the redox status, and (iii) are 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 our recent findings (Lopez-Fabuel et al., 2016) showing that the mitochondrial electron transport chain is differentially organized in neurons and astrocytes. In neurons, complex I is more assembled into supercomplexes than in astrocytes; this result in a higher electron transport efficiency in neurons, and a higher mitochondrial ROS (mROS) production in astrocytes.

Group members
Juan Pedro Bolaños Professor
Emilio Fernández Lecturer
Daniel Jiménez-Blasco Postdoc
Irene Lopez-Fabuel Postdoc
Rubén Quintana-Cabrera Postdoc
Carlos Vicente-Gutiérrez Postdoc
Brenda Morant-Ferrando Predoc
Darwin Israel Manjarrés-Raza Predoc
Ana Olías-Arjona Predoc
Publicaciones recientes
Fernandez-Fernandez S, Bobo-Jimenez V, Requejo-Aguilar R, Gonzalez-Fernandez S, Resch M, Carabias-Carrasco M, Ros J, Almeida A, Bolaños JP (2018)
Hippocampal neurons require a large pool of glutathione to sustain dendrite integrity and cognitive function.
Redox Biol. 19: 52-61
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.
Nature. 509:641-644
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
Research grants
MINECO (SAF2016-78114-R)
CIBERFES (CB16/10/00282)
BATCURE (H2020 grant 666918)
FBBVA
Links of interest
web.usal.es/~jbolanos