Role of aralar, the mitochondrial transporter of aspartate‐glutamate, in brain N‐acetylaspartate formation and Ca<sup>2+</sup> signaling in neuronal mitochondria

Satrústegui, Jorgina; Contreras, Laura; Ramos, Milagros; Mármol, Patricia; Arco, Araceli del; Saheki, Takeyori; Pardo, Beatriz

doi:10.1002/jnr.21299

Cited by 57 publications

(37 citation statements)

References 90 publications

(124 reference statements)

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“…36,37 Consistent with decreased Slc25a21, GSH levels in retinal mitochondria are subnormal in diabetes. 2,3 On the other hand, another small molecule transport protein, Slc25a12, essential for exchange of glutamate and aspartate between cytosol and mitochondria, 38 is upregulated, and its mitochondrial abundance is decreased, suggesting that insertion of slc25a12 into the inner mitochondria and the transport of TCA cycle substrates to the mitochondria are both subnormal in diabetes. As shown in Table 2, diabetes also downregu- lates the membrane polarizing proteins Ucp2 and Gclc, this is consistent with the impaired mitochondrial membrane potential seen in the pathogenesis of diabetic retinopathy and is supported by the report showing a glucose-induced decrease in the Gclc gene in mouse endothelial cells.…”

Section: Discussionmentioning

confidence: 98%

Diabetic Retinopathy and Damage to Mitochondrial Structure and Transport Machinery

Zhong

Kowluru

2011

Invest. Ophthalmol. Vis. Sci.

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Section: Discussionmentioning

confidence: 98%

Diabetic Retinopathy and Damage to Mitochondrial Structure and Transport Machinery

Zhong

Kowluru

2011

Invest. Ophthalmol. Vis. Sci.

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“…The precise role of NAA continues to be investigated. It is a postulated source of acetate for lipid and myelin synthesis of oligodendrocytes (Satrustegui et al, 2007). As the immature rat brain develops, rapid increases in NAA are detected during the time of peak myelination (D'Adamo and Yatsu, 1966;Bates et al, 1989;Burri et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Early and Sustained Alterations in Cerebral Metabolism after Traumatic Brain Injury in Immature Rats

Casey

McKenna

Fiskum

et al. 2008

Journal of Neurotrauma

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Although studies have shown alterations in cerebral metabolism after traumatic brain injury (TBI), clinical data in the developing brain is limited. We hypothesized that post-traumatic metabolic changes occur early (Ͻ24 h) and persist for up to 1 week. Immature rats underwent TBI to the left parietal cortex. Brains were removed at 4 h, 24 h, and 7 days after injury, and separated into ipsilateral (injured) and contralateral (control) hemispheres. Proton nuclear magnetic resonance (NMR) spectra were obtained, and spectra were analyzed for N-acetyl-aspartate (NAA), lactate (Lac), creatine (Cr), choline, and alanine, with metabolite ratios determined (NAA/Cr, Lac/Cr). There were no metabolic differences at any time in sham controls between cerebral hemispheres. At 4 and 24 h, there was an increase in Lac/Cr, reflecting increased glycolysis and/or decreased oxidative metabolism. At 24 h and 7 days, there was a decrease in NAA/Cr, indicating loss of neuronal integrity. The NAA/Lac ratio was decreased (ϳ15-20%) at all times (4 h, 24 h, 7 days) in the injured hemisphere of TBI rats. In conclusion, metabolic derangements begin early (Ͻ24 h) after TBI in the immature rat and are sustained for up to 7 days. Evaluation of early metabolic alterations after TBI could identify novel targets for neuroprotection in the developing brain.

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“…OGC transports α-ketoglutarate from the matrix into the cytoplasm in exchange for malate from the cytoplasm (Fig. 1) (5). An important consequence of MAS activity is that it diverts metabolic flux in mitochondria away from succinyl CoA, succinate, and fumarate (Fig.…”

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Cytosolic reducing power preserves glutamate in retina

Du¹,

Cleghorn²,

Contreras

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Glutamate in neurons is an important excitatory neurotransmitter, but it also is a key metabolite. We investigated how glutamate in a neural tissue is protected from catabolism. Flux analysis using 13 C-labeled fuels revealed that retinas use activities of the malate aspartate shuttle to protect >98% of their glutamate from oxidation in mitochondria. Isolation of glutamate from the oxidative pathway relies on cytosolic NADH/NAD + , which is influenced by extracellular glucose, lactate, and pyruvate. G lutamate is especially important as a metabolite because it is required for the synthesis of glutathione, other amino acids, and proteins. Glutamate also is a key intermediate in glutaminedependent anaplerosis, now known to be a principal source of citric acid cycle intermediates in cancer cells (1).When it is released as a neurotransmitter at brain synapses, glutamate that escapes from the synapse is taken up by astrocytes. There it is converted to glutamine and is delivered back to neurons in a process called the "glutamate/glutamine cycle" (2). Uptake of glutamate and conversion to glutamine within astrocytes stimulates glycolysis and synthesis of lactate. Astrocytes export the lactate to neurons as fuel in a process called the "astrocyte neuron lactate shuttle" (ANLS) (3).Synaptic terminals of rod and cone photoreceptors have characteristics that appear incompatible with the ANLS. The photoreceptor terminal is enriched with transporters for reuptake of glutamate (4), and it encapsulates the synapse. It is unlikely that much glutamate can escape the synapse before being sequestered back into the photoreceptor. We initiated a study to evaluate the role of ANLS in retina. However, the unusual metabolic features of retina revealed a surprising feature of neuronal metabolism, that >98% of glutamate is protected from catabolism. We investigated this protection and show here that the protection is provided by activities associated with the metabolic pathway known as the "malate aspartate shuttle" (MAS) (shown schematically in Fig. 1).MAS activity regenerates cytosolic NAD + that is needed to support glycolysis. To do so, it uses two important transporters to trap the reducing power from cytosolic NADH and shuttle it into the mitochondrial matrix. One transporter is the neuronal aspartate/glutamate carrier (AGC1 or Aralar) (Fig. 1, orange circle); the other transporter is the oxoglutarate carrier (OGC) (Fig. 1, light blue circle). AGC1 transports glutamate from the cytoplasm into the mitochondrial matrix in exchange for aspartate from the matrix (Fig. 1). OGC transports α-ketoglutarate from the matrix into the cytoplasm in exchange for malate from the cytoplasm (Fig. 1) (5). An important consequence of MAS activity is that it diverts metabolic flux in mitochondria away from succinyl CoA, succinate, and fumarate (Fig. 1). Most importantly, glutamate that completes a MAS cycle functions as a catalyst for the importation of reducing power into the mitochondria. The carbon atoms of glutamate are isolated from the oxidative...

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Role of aralar, the mitochondrial transporter of aspartate‐glutamate, in brain N‐acetylaspartate formation and Ca²⁺ signaling in neuronal mitochondria

Cited by 57 publications

References 90 publications

Diabetic Retinopathy and Damage to Mitochondrial Structure and Transport Machinery

Diabetic Retinopathy and Damage to Mitochondrial Structure and Transport Machinery

Early and Sustained Alterations in Cerebral Metabolism after Traumatic Brain Injury in Immature Rats

Cytosolic reducing power preserves glutamate in retina

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Role of aralar, the mitochondrial transporter of aspartate‐glutamate, in brain N‐acetylaspartate formation and Ca2+ signaling in neuronal mitochondria

Cited by 57 publications

References 90 publications

Diabetic Retinopathy and Damage to Mitochondrial Structure and Transport Machinery

Diabetic Retinopathy and Damage to Mitochondrial Structure and Transport Machinery

Early and Sustained Alterations in Cerebral Metabolism after Traumatic Brain Injury in Immature Rats

Cytosolic reducing power preserves glutamate in retina

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Role of aralar, the mitochondrial transporter of aspartate‐glutamate, in brain N‐acetylaspartate formation and Ca²⁺ signaling in neuronal mitochondria