Por favor, use este identificador para citar o enlazar a este item:
http://hdl.handle.net/10261/151680
COMPARTIR / EXPORTAR:
SHARE CORE BASE | |
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL | DATACITE | |
Título: | L-lactate-mediated neuroprotection against glutamate- induced excitotoxicity requires ARALAR/AGC1 |
Autor: | Llorente-Folch, Irene CSIC; Rueda, Carlos B. CSIC; Pérez-Liébana, Irene CSIC; Satrústegui, Jorgina CSIC ORCID; Pardo, Beatriz CSIC ORCID | Palabras clave: | Glutamate excitotoxicity Neuroprotection Malate-aspartate NADH shuttle L-lactate Kainic acid ARALAR/AGC1 |
Fecha de publicación: | 20-abr-2016 | Editor: | Society for Neuroscience | Citación: | Journal of Neuroscience 36: 4443- 4456 (2016) | Resumen: | ARALAR/AGC1/Slc25a12, the aspartate-glutamate carrier from brain mitochondria, is the regulatory step in the malate-aspartate NADH shuttle, MAS. MAS is used to oxidize cytosolic NADH in mitochondria, a process required to maintain oxidative glucose utilization. The role of ARALAR was analyzed in two paradigms of glutamate-induced excitotoxicity in cortical neurons: glucose deprivation and acute glutamate stimulation. ARALAR deficiency did not aggravate glutamate-induced neuronal death in vitro, although glutamate-stimulated respiration was impaired. In contrast, the presence of L-lactate as an additional source protected against glutamate-induced neuronal death in control, but not ARALAR-deficient neurons. L-Lactate supplementation increased glutamate-stimulated respiration partially prevented the decrease in the cytosolic ATP/ADP ratio induced by glutamate and substantially diminished mitochondrial accumulation of 8-oxoguanosine, a marker of reactive oxygen species production, only in the presence, but not the absence, of ARALAR. In addition, L-lactate potentiated glutamate-induced increase in cytosolic Ca, in a way independent of the presence of ARALAR. Interestingly, in vivo, the loss of half-a-dose of ARALAR inaralar mice enhanced kainic acid-induced seizures and neuronal damage with respect to control animals, in a model of excitotoxicity in which increased L-lactate levels and L-lactate consumption have been previously proven. These results suggest that, in vivo, an inefficient operation of the shuttle in the aralar hemizygous mice prevents the protective role of L-lactate on glutamate excitotoxiciy and that the entry and oxidation of L-lactate through ARALAR-MAS pathway is required for its neuroprotective function. SIGNIFICANCE STATEMENT Lactate now stands as a metabolite necessary for multiple functions in the brain and is an alternative energy source during excitotoxic brain injury. Here we find that the absence of a functional malate-aspartate NADH shuttle caused by aralar/AGC1 disruption causes a block in lactate utilization by neurons, which prevents the protective role of lactate on excitotoxicity, but not glutamate excitotoxicity itself. Thus, failure to use lactate is detrimental and is possibly responsible for the exacerbated in vivo excitotoxicity in aralar mice. | URI: | http://hdl.handle.net/10261/151680 | DOI: | 10.1523/JNEUROSCI.3691-15.2016 | Identificadores: | doi: 10.1523/JNEUROSCI.3691-15.2016 issn: 1529-2401 |
Aparece en las colecciones: | (CBM) Artículos |
Ficheros en este ítem:
Fichero | Descripción | Tamaño | Formato | |
---|---|---|---|---|
SatrústeguiJ_L-Lactate-MediatedNeuroprotection.pdf | 11,43 MB | Adobe PDF | Visualizar/Abrir |
CORE Recommender
PubMed Central
Citations
15
checked on 24-mar-2024
SCOPUSTM
Citations
34
checked on 23-mar-2024
WEB OF SCIENCETM
Citations
32
checked on 24-feb-2024
Page view(s)
313
checked on 28-mar-2024
Download(s)
298
checked on 28-mar-2024
Google ScholarTM
Check
Altmetric
Altmetric
Artículos relacionados:
NOTA: Los ítems de Digital.CSIC están protegidos por copyright, con todos los derechos reservados, a menos que se indique lo contrario.