Article

Developmental changes in the Ca2+-regulated mitochondrial aspartate-glutamate carrier aralar1 in brain and prominent expression in the spinal cord.

Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Developmental Brain Research (Impact Factor: 1.78). 07/2003; 143(1):33-46. DOI: 10.1016/S0165-3806(03)00097-X
Source: PubMed

ABSTRACT Aralar1 and citrin are two isoforms of the mitochondrial carrier of aspartate-glutamate (AGC), a calcium regulated carrier, which is important in the malate-aspartate NADH shuttle. The expression and cell distribution of aralar1 and citrin in brain cells has been studied during development in vitro and in vivo. Aralar1 is the only isoform expressed in neurons and its levels undergo a marked increase during in vitro maturation, which is higher than the increase in mitochondrial DNA in the same time window. The enrichment in aralar1 per mitochondria during neuronal maturation is associated with a prominent rise in the function of the malate-aspartate NADH shuttle. Paradoxically, during in vivo development of rat or mouse brain there is very little postnatal increase in total aralar1 levels per mitochondria. This is explained by the fact that astrocytes develop postnatally, have aralar1 levels much lower than neurons, and their increase masks that of aralar1. Aralar1 mRNA and protein are widely expressed throughout neuron-rich areas in adult mouse CNS with clear enrichments in sets of neuronal nuclei in the brainstem and, particularly, in the ventral horn of the spinal cord. These aralar1-rich neurons represent a subset of the cytochrome oxidase-rich neurons in the same areas. The presence of aralar1 could reflect a tonic activity of these neurons, which is met by the combination of high malate-aspartate NADH shuttle and respiratory chain activities.

Download full-text

Full-text

Available from: Araceli del Arco, Jul 04, 2015
1 Follower
 · 
240 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Brain energetic requirements are elevated due to the high cost of impulse transmission and information storage, and are met mainly by glucose oxidation. The energy needs are closely matched by metabolic regulation, which requires the close cooperation of neurons and astrocytes and involves highly regulated fluxes of metabolites between cells. The metabolism in each type of cell is determined in part by its proteomic profile, which has been regarded as complementary. This review will consider the cellular distribution of the mitochondrial aspartate-glutamate carrier, aralar/AGC1/SLC25A12, and its role in the synergic metabolism between neurons and astrocytes. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Neurochemistry International 04/2015; DOI:10.1016/j.neuint.2015.04.001
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The expression of glutaminase in glial cells has been a controversial issue and matter of debate for many years. Actually, glutaminase is essentially considered as a neuronal marker in brain. Astrocytes are endowed with efficient and high capacity transport systems to recapture synaptic glutamate which seems to be consistent with the absence of glutaminase in these glial cells. In this work, a comprehensive study was devised to elucidate expression of glutaminase in neuroglia and, more concretely, in astrocytes. Immunocytochemistry in rat and human brain tissues employing isoform-specific antibodies revealed expression of both Gls and Gls2 glutaminase isozymes in glutamatergic and GABAergic neuronal populations as well as in astrocytes. Nevertheless, there was a different subcellular distribution: Gls isoform was always present in mitochondria while Gls2 appeared in two different locations, mitochondria and nucleus. Confocal microscopy and double immunofluorescence labeling in cultured astrocytes confirmed the same pattern previously seen in brain tissue samples. Astrocytic glutaminase expression was also assessed at the mRNA level, real-time quantitative RT-PCR detected transcripts of four glutaminase isozymes but with marked differences on their absolute copy number: the predominance of Gls isoforms over Gls2 transcripts was remarkable (ratio of 144:1). Finally, we proved that astrocytic glutaminase proteins possess enzymatic activity by in situ activity staining: concrete populations of astrocytes were labeled in the cortex, cerebellum and hippocampus of rat brain demonstrating functional catalytic activity. These results are relevant for the stoichiometry of the Glu/Gln cycle at the tripartite synapse and suggest novel functions for these classical metabolic enzymes. GLIA 2014
    Glia 03/2015; 63(3):365-382. DOI:10.1002/glia.22758
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondria play an important role in adaptation of organisms to changing environmental conditions and type of food. Human mitochondrial DNA (mtDNA) has discrete branches with a group of related mtDNA sequences called a haplogroup. D. C. Wallace stressed that people with different haplogroups have different predisposition to various pathological conditions [1]. Mitochondrial dysfunctions are important in pathogenesis of many major pathologies, particularly neurodegenerative diseases. In this review we analyze the current hypotheses regarding energy metabolism of the brain’s two major cell types - neurons and astroglia. Recently, it was clearly shown that up to 20% of the total brain’s energy is provided by mitochondrial oxidation of fatty acids. However, the existing hypotheses consider glucose, or its derivative lactate, as the only main energy substrates for the brain. Astroglia metabolically supports the neurons by providing lactate as a substrate for neuronal mitochondria. In addition, a significant amount of neuromediators, glutamate and GABA, are transported into neurons and also serve as substrates for mitochondria. Thus neuronal mitochondria may simultaneously oxidize several substrates. Astrocytes have important function to replenish the pool of neuromediators by synthesis de novo, which requires large amounts of energy. In this review we made an attempt to reconcile β-oxidation of fatty acids by astrocytic mitochondria with the existing hypothesis on regulation of aerobic glycolysis. As a result, it becomes clear that under condition of neuronal excitation, both metabolic pathways may exist simultaneously. We also provide experimental evidence that isolated neuronal mitochondria may oxidize palmitoyl carnitine in the presence of other mitochondrial substrates. We briefly discuss the possible roles of variations in mitochondrial metabolic phenotypes in predisposition to neurodegenerative diseases among individuals belonging to different mtDNA haplogroups.
    BioMed Research International 05/2014; In press(The Road to Mitochondrial Dysfunctions). DOI:10.1155/2014/472459