Recently, we have reported that the inhibition of mitochondrial respiration by nitric oxide (NO) leads to an up-regulation of glycolysis and affords cytoprotection against energy failure through the stimulation of AMPK (5′-AMP-activated protein kinase) [Almeida, Moncada and Bolaños (2004) Nat. Cell Biol. 6, 45–51]. To determine whether glucose transport contributes specifically to this effect, we have now investigated the possible role of NO in modulating glucose uptake through GLUT3, a facilitative high-affinity glucose carrier that has been suggested to afford cytoprotection against hypoglycaemic episodes. To do so, GLUT3-lacking HEK-293T cells (human embryonic kidney 293T cells) were transformed to express a plasmid construction encoding green fluorescent protein-tagged GLUT3 cDNA. This carrier was preferentially localized to the plasma membrane, was seen to be functionally active and afforded cytoprotection against low glucose-induced apoptotic death. Inhibition of mitochondrial respiration by NO triggered a rapid, cGMP-independent enhancement of GLUT3-mediated glucose uptake through a mechanism that did not involve transporter translocation. Furthermore, the functional disruption of AMPK by the RNA interference strategy rendered cells unable to respond to NO by activating GLUT3-mediated glucose uptake. These results suggest that the inhibition of mitochondrial respiration by NO activates AMPK to stimulate glucose uptake, thereby representing a novel survival pathway during pathophysiological conditions involving transient reductions in the supply of cellular glucose.
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Research Article|
December 07 2004
Inhibition of mitochondrial respiration by nitric oxide rapidly stimulates cytoprotective GLUT3-mediated glucose uptake through 5′-AMP-activated protein kinase
Pilar CIDAD;
Pilar CIDAD
*Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain
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Angeles ALMEIDA;
Angeles ALMEIDA
*Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain
†Unidad de Investigación, Hospital Universitario de Salamanca, Salamanca, Spain
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Juan P. BOLAÑOS
Juan P. BOLAÑOS
1
*Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain
‡Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
1To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
May 26 2004
Revision Received:
August 03 2004
Accepted:
August 23 2004
Accepted Manuscript online:
August 23 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2004
Biochem J (2004) 384 (3): 629–636.
Article history
Received:
May 26 2004
Revision Received:
August 03 2004
Accepted:
August 23 2004
Accepted Manuscript online:
August 23 2004
Citation
Pilar CIDAD, Angeles ALMEIDA, Juan P. BOLAÑOS; Inhibition of mitochondrial respiration by nitric oxide rapidly stimulates cytoprotective GLUT3-mediated glucose uptake through 5′-AMP-activated protein kinase. Biochem J 15 December 2004; 384 (3): 629–636. doi: https://doi.org/10.1042/BJ20040886
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