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.

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