Glutamate: Where does it come from and where does it go?

Olsen, Grethe M.; Sonnewald, Ursula

doi:10.1016/j.neuint.2014.11.006

Cited by 25 publications

(30 citation statements)

References 35 publications

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“…It was shown that partial pyruvate recycling, i.e., lactate formation from the TCA cycle (Figure ), did increase with increasing extracellular glutamate concentrations in astrocytes (McKenna, Sonnewald, Huang, Stevenson, & Zielke, ). Combining the results from several publications (Olsen & Sonnewald, ), this coupling between the external glutamate concentration and lactate formation was confirmed and lactate production from the TCA cycle was shown to be more active in astrocytes than neurons, in line with the astrocytes’ greater capacity for glutamate uptake.…”

Section: Discussionsupporting

confidence: 70%

“…This recycling was originally believed to take place primarily in neurons and not in astrocytes because labeling patterns related to recycling were apparent in glutamate but not glutamine. Subsequent studies did, however, lead to the conclusion that this process is active in both astrocytes and neurons (Olsen & Sonnewald, ). The process of pyruvate recycling in the brain was additionally demonstrated in other animal studies (Haberg et al, ; Melo, Sonnewald, Touret, & Nehlig, ; Morken et al, ; Sonnewald, Therrien, & Butterworth, ).…”

Section: Discussionmentioning

confidence: 99%

Section: Balancing Anaplerosis With Cataplerosismentioning

confidence: 99%

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Astrocytic pyruvate carboxylation: Status after 35 years

Schousboe

Waagepetersen

Sonnewald

2019

J of Neuroscience Research

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The first two publications dealing with the question of the cellular localization of the enzyme pyruvate carboxylase (PC) which in the brain represents the most important metabolic pathway to allow anaplerosis of TCA cycle constituents were published in 1983 and 1985. Hence, 2018 marks the 35th anniversary of the notion based on the results of the publications provided above that PC‐catalyzed anaplerosis in the brain is an astrocytic process. This review will provide the background for investigating this enzymatic pathway as well as a discussion of cataplerosis, the degradation of products from anaplerosis, and the current status of the functional significance of pyruvate carboxylation in brain metabolism.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Balancing Anaplerosis With Cataplerosismentioning

confidence: 99%

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Astrocytic pyruvate carboxylation: Status after 35 years

Schousboe

Waagepetersen

Sonnewald

2019

J of Neuroscience Research

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“…Glutamate is a precursor of glutamine and other molecules such as GABA, glutathione and 2-oxoglutarate. Glutamate is also a neurotransmitter (Olsen & Sonnewald, 2015) and fetal plasma levels must be carefully controlled during fetal brain development because high levels of glutamate are neurotoxic (Tian et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Evidence of adaptation of maternofetal transport of glutamine relative to placental size in normal mice, and in those with fetal growth restriction

McIntyre

Hayward

Sibley

et al. 2019

The Journal of Physiology

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Key points Fetal growth restriction (FGR) is a major risk factor for stillbirth and has significant impact upon lifelong health. A small, poorly functioning placenta, as evidenced by reduced transport of nutrients to the baby, underpins FGR. It remains unclear how a small but normal placenta differs from the small FGR placenta in terms of ability to transfer nutrients to the fetus. Placental transport of glutamine and glutamate, key amino acids for fetal growth, was assessed in normal mice and those with FGR. Glutamine and glutamate transport was greater in the lightest versus heaviest placenta in a litter of normally grown mice. Placentas of mice with FGR had increased transport capacity in mid‐pregnancy, but this adaptation was insufficient in late pregnancy. Placental adaptations, in terms of increased nutrient transport (per gram) to compensate for small size, appear to achieve appropriate fetal growth in normal pregnancy. Failure of this adaptation might contribute to FGR. Abstract Fetal growth restriction (FGR), a major risk factor for stillbirth, and neonatal and adulthood morbidity, is associated with reduced placental size and decreased placental nutrient transport. In mice, a small, normal placenta increases its nutrient transport, thus compensating for its reduced size and maintaining normal fetal growth. Whether this adaptation occurs for glutamine and glutamate, two key amino acids for placental metabolism and fetal growth, is unknown. Additionally, an assessment of placental transport of glutamine and glutamate between FGR and normal pregnancy is currently lacking. We thus tested the hypothesis that the transport of glutamine and glutamate would be increased (per gram of tissue) in a small normal placenta [C57BL6/J (wild‐type, WT) mice], but that this adaptation fails in the small dysfunctional placenta in FGR [insulin‐like growth factor 2 knockout (P0) mouse model of FGR]. In WT mice, comparing the lightest versus heaviest placenta in a litter, unidirectional maternofetal clearance (Kmf) of 14C‐glutamine and 14C‐glutamate (glutamineKmf and glutamateKmf) was significantly higher at embryonic day (E) 18.5, in line with increased expression of LAT1, a glutamine transporter protein. In P0 mice, glutamineKmf and glutamateKmf were higher (P0 versus wild‐type littermates, WTL) at E15.5. At E18.5, glutamineKmf remained elevated whereas glutamateKmf was similar between groups. In summary, we provide evidence that glutamineKmf and glutamateKmf adapt according to placental size in WT mice. The placenta of the growth‐restricted P0 fetus also elevates transport capacity to compensate for size at E15.5, but this adaptation is insufficient at E18.5; this may contribute to decreased fetal growth.

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“…Correspondingly, the PAPs are well-known to contain high affinity glutamate transporters and glutamine synthetase [19,20]. The open issue, however, remains how these two energy demanding processes are fueled, and whether the PAP exhibits oxidative capability (for reviews see [21,22]). The glial fate of transmitter glutamate and origin of glutamine may also be linked to anaplerotic mitochondria-bound pathways or energy metabolism within the PAPs (for review see [23]).…”

Section: Introductionmentioning

confidence: 99%

Fine Astrocyte Processes Contain Very Small Mitochondria: Glial Oxidative Capability May Fuel Transmitter Metabolism

2015

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The peripheral astrocyte process (PAP) is the glial compartment largely handling inactivation of transmitter glutamate, and supplying glutamate to the axon terminal. It is not clear how these energy demanding processes are fueled, and whether the PAP exhibits oxidative capability. Whereas the GFAP-positive perinuclear cytoplasm and stem process are rich in mitochondria, the PAP is often considered too narrow to contain mitochondria and might thus not rely on oxidative metabolism. Applying high resolution light microscopy, we investigate here the presence of mitochondria in the PAPs of freshly dissociated, isolated astrocytes. We provide an overview of the subcellular distribution and the approximate size of astrocytic mitochondria. A substantial proportion of the astrocyte's mitochondria are contained in the PAPs and, on the average, they are smaller there than in the stem processes. The majority of mitochondria in the stem and peripheral processes are surprisingly small (0.2-0.4 µm), spherical and not elongate, or tubular, which is supported by electron microscopy. The density of mitochondria is two to several times lower in the PAPs than in the stem processes. Thus, PAPs do not constitute a mitochondria free glial compartment but contain mitochondria in large numbers. No juxtaposition of mitochondria-containing PAPs and glutamatergic synapses has been reported. However, the issue of sufficient ATP concentrations in perisynaptic PAPs can be seen in the light of (1) the rapid, activity dependent PAP motility, and (2) the recently reported activity-dependent mitochondrial transport and immobilization leading to spatial, subcellular organisation of glutamate uptake and oxidative metabolism.

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Glutamate: Where does it come from and where does it go?

Cited by 25 publications

References 35 publications

Astrocytic pyruvate carboxylation: Status after 35 years

Astrocytic pyruvate carboxylation: Status after 35 years

Evidence of adaptation of maternofetal transport of glutamine relative to placental size in normal mice, and in those with fetal growth restriction

Fine Astrocyte Processes Contain Very Small Mitochondria: Glial Oxidative Capability May Fuel Transmitter Metabolism

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