Neuronal and astrocytic shuttle mechanisms for cytosolic-mitochondrial transfer of reducing equivalents: current evidence and pharmacological tools.

  title={Neuronal and astrocytic shuttle mechanisms for cytosolic-mitochondrial transfer of reducing equivalents: current evidence and pharmacological tools.},
  author={Mary Clare McKenna and Helle S{\o}nderby Waagepetersen and Arne Schousboe and Ursula Sonnewald},
  journal={Biochemical pharmacology},
  volume={71 4},

Redox Shuttles in the Brain

The malate-aspartate shuttle is considered to be the major redox shuttle system transferring reducing equivalents from cytosolic NAD+/NADH to mitochondria that functions in brain, mainly important in neuronal cells.

Malate-Aspartate Shuttle Inhibitor Aminooxyacetate Acid Induces Apoptosis and Impairs Energy Metabolism of Both Resting Microglia and LPS-Activated Microglia

This study determined the roles of MAS in the survival and energy metabolism of microglia by using aminooxyacetate acid (AOAA)—a widely used MAS inhibitor and suggested that AOAA can effectively inhibit the MAS activity of the cells.

Malate-aspartate shuttle mediates the intracellular ATP levels, antioxidation capacity and survival of differentiated PC12 cells.

This study used differentiated PC12 cells as a cellular model to investigate the roles of NADH shuttle in the energy metabolism, antioxidation capacity and survival of cells, and found that MAS inhibition led to a significant decrease in the levels of GSH - a major antoxidation molecule in cells, suggesting an important role of MAS in maintaining the antiox oxidation capacity of cells.

Mitochondrial transport proteins of the brain

The data suggest a compartmentation of glucose metabolism in which astrocytes catalyze glycolytic conversion of glucose to lactate, whereas neurons are capable of oxidizing both lactate and glucose to CO2 + H2O.

The importance of redox shuttles to pancreatic beta-cell energy metabolism and function.

This work may provide evidence for a central role of Aralar1 in the regulation of nutrient metabolism in the beta-cells, as potentiating or attenuating activities of various amino acids on insulin secretion, mitochondrial membrane potential and NADH production in ArAlar1-overexpressing beta- cells are investigated.

Ischemic Neuroprotectant PKCε Restores Mitochondrial Glutamate Oxaloacetate Transaminase in the Neuronal NADH Shuttle after Ischemic Injury

Novel protective targets and mechanisms against ischemic injury, which involves PKCε-mediated phosphorylation and activation of GOT2 in the malate-aspartate shuttle are revealed.

Novel Inhibitors of Mitochondrial sn-Glycerol 3-phosphate Dehydrogenase

These novel mGPDH inhibitors are unique tools to investigate the role of glycerol 3-phosphate metabolism in both isolated and intact systems and found to be mixed inhibitors with IC50 and K i values between ∼1–15 µM.

NBCe1 mediates the regulation of the NADH/NAD+ redox state in cortical astrocytes by neuronal signals

The results demonstrate that the NADH/NAD+ redox state in astrocytes is a metabolic node regulated by neuronal signals reflecting physiological activity, most likely contributing to adjust astroCytic metabolism to energy demand of the brain.

Glutamate oxidation in astrocytes: Roles of glutamate dehydrogenase and aminotransferases

Results, in conjunction with reports in the literature, support the conclusion that GDH is active in astrocytes both in culture and in vivo and that this enzyme plays a significant role in glutamate oxidation.



Glutamate Neurotoxicity in Rat Cerebellar Granule Cells Involves Cytochrome c Release from Mitochondria and Mitochondrial Shuttle Impairment

The increase in the cell NADH fluorescence was found to be time‐dependent, an index of the progressive damage of the cell, and both the two mitochondrial shuttles glycerol 3‐phosphate/dihydroxyacetone phosphate and malate/oxaloacetate, devoted to oxidizing externally added NADH, were found to been impaired under glutamate neurotoxicity.

Reduced N-Acetylaspartate Levels in Mice Lacking Aralar, a Brain- and Muscle-type Mitochondrial Aspartate-glutamate Carrier*

Results show that aralar plays an important role in myelin formation by providing aspartate for the synthesis of N-acetylaspartate in neuronal cells.

Influence of the Malate‐Aspartate Shuttle on Oxidative Metabolism in Synaptosomes

Abstract: β‐Methyleneaspartate, a specific inhibitor of aspartate aminotransferase (EC, was used to investigate the role of the malate‐aspartate shuttle in rat brain synaptosomes.

Neuronal uptake and metabolism of glycerol and the neuronal expression of mitochondrial glycerol‐3‐phosphate dehydrogenase

It was found that intracerebral injection of [14C]glycerol in rat gave a higher specific activity of glutamate than of glutamine, indicating neuronal metabolism of glycerol, and the localization of mitochondrial and cytosolic Glycerol‐3‐phosphate dehydrogenases in different cell types implies that the glycerian shuttle is of little importance in the brain.

Elucidation of the quantitative significance of pyruvate carboxylation in cultured cerebellar neurons and astrocytes

The present study has unequivocally demonstrated a quantitatively important pyruvate carboxylation in astrocytes but it was not possible to demonstrate the presence of such carboxYLation in neurons, and based on the present results it may be safely concluded that neuronal pyruVate car boxylation is unlikely to be of quantitative significance.

Aspartate aminotransferase, malate dehydrogenase, and pyruvate carboxylase activities in rat cerebral synaptic and nonsynaptic mitochondria: Effects ofin vitro treatment with ammonia, hyperammonemia and hepatic encephalopathy

The effects of in vitro treatment with ammonium chloride, hepatic encephalopathy (HE) due to thioacetamide (TAA) induced liver failure and chronic hyperammonemia produced by i. p. administration of

The regulation and glutamate metabolism by tricarboxylic acid-cycle activity in rat brain mitochondria

Evidence is provided from a reconstituted malate–aspartate cycle with brain mitochondria that increased C2 flux into the tricarboxylic acid cycle from pyruvate may inhibit the reoxidation of exogenous NADH.

Regulation of energy metabolism in synaptic terminals and cultured rat brain astrocytes: differences revealed using aminooxyacetate.

The findings demonstrate that inhibiting transamination with AOAA had very different effects on the oxidation of energy substrates in the two preparations, suggesting that the regulation of metabolism is quite different in astrocytes and synaptic terminals.