Calcium-Regulation of Mitochondrial Respiration Maintains ATP Homeostasis and Requires ARALAR/AGC1-Malate Aspartate Shuttle in Intact Cortical Neurons

Llorente‐Folch, Irene; Rueda, Carlos B.; Amigo, Ignácio; Arco, Araceli del; Saheki, Takeyori; Pardo, Beatriz; Satrústegui, Jorgina

doi:10.1523/jneurosci.0929-13.2013

Cited by 95 publications

(154 citation statements)

References 62 publications

(2 reference statements)

Supporting

Mentioning

142

Contrasting

Order By: Relevance

“…However, it must be kept in mind that the experiments on MAS inhibition by matrix Ca 2? in isolated mitochondria were carried out in the absence of pyruvate (or lactate as pyruvate donor). As indicated by Gellerich [16] in isolated mitochondria and by Llorente-Folch et al [19,21] and Rueda et al [22] for intact neurons, the main function of MAS activation is to stimulate pyruvate uptake in mitochondria, and it is possible that the extra supply of pyruvate caused by Ca 2? -activation of MAS prevents a fall in a-KG levels and inhibition of the OGC.…”

Section: Malate Aspartate Shuttle In Isolated Brain Mitochondria and mentioning

confidence: 92%

See 1 more Smart Citation

Fluctuations in Cytosolic Calcium Regulate the Neuronal Malate–Aspartate NADH Shuttle: Implications for Neuronal Energy Metabolism

Satrústegui

Bak

2015

Neurochem Res

View full text Add to dashboard Cite

The malate-aspartate NADH shuttle (MAS) operates in neurons and other cells to translocate reducing equivalents from the cytosol to the mitochondrial matrix, thus allowing a continued flux through the glycolytic pathway and metabolism of extracellular lactate. Recent discoveries have taught us that MAS is regulated by fluctuations in cytosolic Ca 2? levels, and that this regulation is required to maintain a tight coupling between neuronal activity and mitochondrial respiration and oxidative phosphorylation. At cytosolic Ca 2? fluctuations below the threshold of the mitochondrial calcium uniporter, there is a positive correlation between Ca 2? and MAS activity; however, if cytosolic Ca 2? increases above the threshold, MAS activity is thought to be reduced by an intricate mechanism. The latter forces the neurons to partly rely on anaerobic glycolysis producing lactate that may be metabolized subsequently, by neurons or other cells. In this review, we will discuss the evidence for Ca 2? -mediated regulation of MAS that have been uncovered over the last decade or so, together with the need for further verification, and examine the metabolic ramifications for neurons.

show abstract

Section: Malate Aspartate Shuttle In Isolated Brain Mitochondria and mentioning

confidence: 92%

“…in oxygen consumption of cerebellar neurons [18]. These issues have been recently addressed in cerebrocortical neurons using physiological glucose concentrations [19]. Calcium was clearly shown to play a role in regulating workload-stimulated neuronal respiration.…”

Section: Introductionmentioning

confidence: 99%

Fluctuations in Cytosolic Calcium Regulate the Neuronal Malate–Aspartate NADH Shuttle: Implications for Neuronal Energy Metabolism

Satrústegui

Bak

2015

Neurochem Res

View full text Add to dashboard Cite

show abstract

“…Singlecell measurements of cytosolic Ca 2ϩ and Na ϩ were performed as previously described (Llorente-Folch et al, 2013) using neurons loaded with fura-2 AM as Ca 2ϩ indicator (Ruiz et al, 1998;Pardo et al, 2006) and SBFI as Na ϩ indicator (Rose and Ransom, 1997) at 37°C. Experiments were performed in HEPES-control salt solution (HCSS) containing 15 mM glucose with 2 mM CaCl 2 .…”

Section: Methodsmentioning

confidence: 99%

“…Ca 2ϩ activation of ARALAR increases pyruvate formation and supply into mitochondria, which increases mitochondrial matrix NADH production and respiration. Moreover, the ARALAR-MAS pathway is required to upregulate respiration under conditions of increased workload in neurons using glucose (Llorente-Folch et al, 2013;Rueda et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

l-Lactate-Mediated Neuroprotection against Glutamate-Induced Excitotoxicity Requires ARALAR/AGC1

et al. 2016

Self Cite

View full text Add to dashboard Cite

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 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 Ca 2ϩ , in a way independent of the presence of ARALAR. Interestingly, in vivo, the loss of half-a-dose of ARALAR in aralar ϩ/Ϫ 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.

show abstract

“…This depletion of Ca 2ϩ on both sides of the cluster (63) could have a substantial impact on metabolic activities in these mitochondria (32,38). Ca 2ϩ influences mitochondrial activities in neurons (31,32,39). Increased cytosolic Ca 2ϩ can stimulate the aspartate/glutamate carrier 1 (AGC1), which transports aspartate from the A, in darkness 3Ј:5Ј cGMP is not rapidly hydrolyzed to 5Ј-GMP.…”

Section: Control Of Metabolism By Signalingmentioning

confidence: 99%

Phototransduction Influences Metabolic Flux and Nucleotide Metabolism in Mouse Retina

Rountree

Cleghorn³

et al. 2016

Journal of Biological Chemistry

100

View full text Add to dashboard Cite

Production of energy in a cell must keep pace with demand.Photoreceptors use ATP to maintain ion gradients in darkness, whereas in light they use it to support phototransduction. Matching production with consumption can be accomplished by coupling production directly to consumption. Alternatively, production can be set by a signal that anticipates demand. In this report we investigate the hypothesis that signaling through phototransduction controls production of energy in mouse retinas. We found that respiration in mouse retinas is not coupled tightly to ATP consumption. By analyzing metabolic flux in mouse retinas, we also found that phototransduction slows metabolic flux through glycolysis and through intermediates of the citric acid cycle. We also evaluated the relative contributions of regulation of the activities of ␣-ketoglutarate dehydrogenase and the aspartate-glutamate carrier 1. In addition, a comprehensive analysis of the retinal metabolome showed that phototransduction also influences steady-state concentrations of 5-GMP, ribose-5-phosphate, ketone bodies, and purines. Warburg et al.(1) and Krebs (2) reported in the 1920s that tumors and retinas rely on aerobic glycolysis. Some of the biochemical mechanisms by which cancer cells adapt to aerobic glycolysis have been gleaned from investigations of specific metabolic adaptations of cancer cells either in culture or in a tumor (3, 4). Retinas offer distinct advantages for investigating aerobic glycolysis. They have high metabolic rates, a uniquely laminated structure, and the primary signaling pathway by which retinas respond to light is defined clearly.Retinas convert 80 -96% of glucose they consume into lactic acid (5-9), similar to the extent of aerobic glycolysis that fuels cancer cells (3). Aerobic glycolysis occurs primarily in photoreceptors (10) where the energy demands are very different in darkness than in light (5,7,(11)(12)(13). In darkness energy is consumed within the inner segments to support ion pumping (5, 13). In light energy is consumed by the outer segments (OS) 2 to support phototransduction and regeneration of visual pigments. A photoreceptor neuron also performs anabolic metabolism to replace the ϳ10% of its OS material that is lost each day to phagocytosis by the retinal pigmented epithelium (14, 15).Some of the carbons in glucose consumed by a retina reach the mitochondrial matrix where they are oxidized in biochemical reactions that reduce NAD ϩ to NADH. Transfer of electrons from NADH to O 2 then generates a proton gradient across the mitochondrial inner membrane. In some tissues dissipation of the proton gradient is coupled tightly to ATP demand. In others, proton leakage can dissipate the gradient even without ATP synthesis (16). In this report we show that mitochondria in retinas are more uncoupled than mitochondria in other tissues.The ability of a photoreceptor to respond to light, to release neurotransmitter, to regenerate visual pigment, to renew itself, and to remain viable requires that production of energy keeps pace...

show abstract

Calcium-Regulation of Mitochondrial Respiration Maintains ATP Homeostasis and Requires ARALAR/AGC1-Malate Aspartate Shuttle in Intact Cortical Neurons

Abstract: Neuronal respiration is controlled by ATP demand and

Cited by 95 publications

References 62 publications

Fluctuations in Cytosolic Calcium Regulate the Neuronal Malate–Aspartate NADH Shuttle: Implications for Neuronal Energy Metabolism

Fluctuations in Cytosolic Calcium Regulate the Neuronal Malate–Aspartate NADH Shuttle: Implications for Neuronal Energy Metabolism

l-Lactate-Mediated Neuroprotection against Glutamate-Induced Excitotoxicity Requires ARALAR/AGC1

Phototransduction Influences Metabolic Flux and Nucleotide Metabolism in Mouse Retina

Contact Info

Product

Resources

About