| First Author | Llorente-Folch I | Year | 2016 |
| Journal | J Neurosci | Volume | 36 |
| Issue | 16 | Pages | 4443-56 |
| PubMed ID | 27098689 | Mgi Jnum | J:231959 |
| Mgi Id | MGI:5775667 | Doi | 10.1523/JNEUROSCI.3691-15.2016 |
| Citation | Llorente-Folch I, et al. (2016) l-Lactate-Mediated Neuroprotection against Glutamate-Induced Excitotoxicity Requires ARALAR/AGC1. J Neurosci 36(16):4443-56 |
| abstractText | 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 deathin vitro, although glutamate-stimulated respiration was impaired. In contrast, the presence ofl-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(2+), 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 increasedl-lactate levels andl-lactate consumption have been previously proven. These results suggest that,in vivo, an inefficient operation of the shuttle in thearalarhemizygous mice prevents the protective role ofl-lactate on glutamate excitotoxiciy and that the entry and oxidation ofl-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 byaralar/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 exacerbatedin vivoexcitotoxicity inaralar(+/-)mice. |
