期刊
JOURNAL OF NEUROSCIENCE
卷 36, 期 16, 页码 4443-4456出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3691-15.2016
关键词
ARALAR/AGC1; glutamate excitotoxicity; kainic acid; L-lactate; malate-aspartate NADH shuttle; neuroprotection
资金
- Ministerio de Economia Grant [BFU2011-30456, SAF2014-56929R]
- Centro de Investigacion Biomedica en Red de Enfermedades Raras (an initiative of the Instituto de Salud Carlos III)
- Comunidad de Madrid Grant [S2010/BMD-2402 MITOLAB-CM]
- Ministerio de Economia y Competitividad
ARALAR/AGC1/Slc25a12, the aspartate-glutamate carrier from brain mitochondria, is the regulatory step in the malate-aspartateNADH 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. ARALARdeficiency 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 Ca2+, in a way independent of the presence of ARALAR. Interestingly, in vivo, the loss of half-a-dose of ARALAR in aralar(+/-) 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.
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