Referencia

Nature Cell Biol. 2009 Jun;11(6):747-752

Autores

Herrero-Méndez, A.; Almeida, A.; Fernández, E.; Maestre, C.; Moncada, S.; y Bolaños, J.P.

Resumen

Neurons are known to have a lower glycolytic rate than astrocytes and when stressed they are unable to upregulate glycolysis because of low Pfkfb3 (6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase-3) activity. This enzyme generates fructose-2,6-bisphosphate (F2,6P(2)), the most potent activator of 6-phosphofructo-1-kinase (Pfk1; ref. 4), a master regulator of glycolysis. Here, we show that Pfkfb3 is absent from neurons in the brain cortex and that Pfkfb3 in neurons is constantly subject to proteasomal degradation by the action of the E3 ubiquitin ligase, anaphase-promoting complex/cyclosome (APC/C)-Cdh1. By contrast, astrocytes have low APC/C-Cdh1 activity and therefore Pfkfb3 is present in these cells. Upregulation of Pfkfb3 by either inhibition of Cdh1 or overexpression of Pfkfb3 in neurons resulted in the activation of glycolysis. This, however, was accompanied by a marked decrease in the oxidation of glucose through the pentose phosphate pathway (a metabolic route involved in the regeneration of reduced glutathione) resulting in oxidative stress and apoptotic death. Thus, by actively downregulating glycolysis by APC/C-Cdh1, neurons use glucose to maintain their antioxidant status at the expense of its utilization for bioenergetic purposes.

Descripción

Las neuronas tienen una escasísima actividad de la 6-fosfofructo-2quinasa-2/fructosa-2,6-bifosfatasa (isoforma 3 o Pfkfb3), que sintetiza fructosa-2,6-bifosfato, un efector alostérico positivo de la fosfofructoquinasa-1. En este trabajo se muestra que la Pfkfb3 es un sustrato de la E3 ubiquitina ligasa APC/ C (anaphase-promoting complex/cyclosome), y su cofactor Cdh1, para su ubiquitinación. Así, mediante un activo sistema de regulación negativa de la glucólisis, las neuronas utilizan glucosa preferentemente en la vía de las fosfatopentosas y así protegerse del estrés oxidativo.

Imagen artículo Enero

REFERENCIA DEL GRUPO E INVESTIGADOR
Ángel Herrero Méndez realizó su tesis doctoral en el grupo de Juan Pedro Bolaños (Instituto de Neurociencias de Castilla y Leon-Universidad de Salamanca). El grupo está interesado en conocer los mecanismos de regulación fisiopatológica en el sistema nervioso en relación con la etiología de la Enfermedad de Parkinson. Actualmente Ángel Herrero desarrolla su investigación en el campo de la ingeniería tisular y la terapia celular en la empresa Histocell.

AUTORES DEL ARTÍCULO:
• Ángel Herrero Méndez. Departamento de Bioquimica y Biologia Molecular, Universidad de Salamanca, Instituto de Neurociencias de Castilla y Leon.
• Ángeles Almeida. Departamento de Bioquimica y Biologia Molecular, Universidad de Salamanca, Instituto de Neurociencias de Castilla y Leon. Unidad de Investigacion, Hospital Universitario de Salamanca, Instituto de Estudios de Ciencias de la Salud de Castilla y Leon.
• Emilio Fernández. Departamento de Bioquimica y Biologia Molecular, Universidad de Salamanca, Instituto de Neurociencias de Castilla y Leon.
• Carolina Maestre. Departamento de Bioquimica y Biologia Molecular, Universidad de Salamanca, Instituto de Neurociencias de Castilla y Leon. Unidad de Investigacion, Hospital Universitario de Salamanca, Instituto de Estudios de Ciencias de la Salud de Castilla y Leon.
• Salvador Moncada. Wolfson Institute for Biomedical Research, University College London.
• Juan Pedro Bolaños. Departamento de Bioquimica y Biologia Molecular, Universidad de Salamanca, Instituto de Neurociencias de Castilla y Leon.

Descárgate este artículo aquí

¿Acabas de publicar un artículo interesante?

Manda la referencia a través de nuestro formulario.  Límite de edad 32 años. Los artículos seleccionados serán destacados como artículos del mes y participarán en el Premio al mejor artículo de jóvenes de la SEBBM, que se entregará en el congreso de la SEBBM (inscripción y alojamiento gratuitos).

Otros "Artículos del mes"

Self-Assembling ELR-Based Nanoparticles as Smart Drug-Delivery Systems Modulating Cellular Growth via Akt

15-10-2019

This work investigates the physicochemical properties and in vitro accuracy of a genetically engineered drug delivery system based on elastin-like block recombinamers. The DNA recombinant technics allowed us to create...

Leer más

Structure–Function of MamC Loop and Its Effect on the *in Vitro* Precipitation of Biomimetic Magnetite Nanoparticles

01-09-2019

MamC, an integral protein of the magnetosome membrane, has recently been proposed as a strong candidate to produce biomimetic (magnetosome-like) magnetite nanoparticles that could be used as an alternative to...

Leer más

Sticholysin, Sphingomyelin, and Cholesterol: A Closer Look at a Tripartite Interaction

01-08-2019

Actinoporins are a group of soluble toxic proteins that bind to membranes containing sphingomyelin (SM) and oli- gomerize to form pores. Sticholysin II (StnII) is a member of the actinoporin...

Leer más

Astrocytic mitochondrial ROS modulate brain metabolism and mouse behaviour

01-07-2019

To satisfy its high energetic demand, the brain depends on the metabolic cooperation of various cell types. For example, astrocytic-derived lactate sustains memory consolidation by serving both as an oxidizable...

Leer más

Glucose restriction promotes osteocyte specification by activating a PGC-1α-dependent transcriptional program

03-06-2019

Osteocytes, the most abundant of bone cells, differentiate while they remain buried within the bone matrix. This encasement limits their access to nutrients and likely affects their differentiation, a process...

Leer más

ParB dynamics and the critical role of the CTD in DNA condensation unveiled by combined force-fluorescence measurements

01-05-2019

/Bacillus subtilis/ ParB forms multimeric networks involving non-specific DNA binding leading to DNA condensation. Previously, we found that an excess of the free C-terminal domain (CTD) of ParB impeded DNA...

Leer más

Therapeutic targeting of HER2-CB2R heteromers in HER2-positive breast cancer

01-04-2019

Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New...

Leer más

p73 regulates ependymal planar cell polarity by modulating actin and microtubule cytoskeleton

01-03-2019

Planar cell polarity (PCP) and intercellular junctional complexes establish tissue structure and coordinated behaviors across epithelial sheets. In multiciliated ependymal cells, rotational and translational PCP coordinate cilia beating and direct...

Leer más

β‐RA reduces DMQ/CoQ ratio and rescues the encephalopathic phenotype in Coq9R239X mice

01-02-2019

Coenzyme Q (CoQ) deficiency has been associated with primary defects in the CoQ biosynthetic pathway or to secondary events. In some cases, the exogenous CoQ supplementation has limited efficacy. In...

Leer más

Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons

02-01-2019

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of...

Leer más

Socios Protectores