Divergent Cellular Energetics, Glutamate Metabolism, and Mitochondrial Function Between Human and Mouse Cerebral Cortex

Westi, Emil W.; Jakobsen, Emil; Voss, Caroline M.; Bak, Lasse K.; Pinborg, Lars H.; Aldana, Blanca I.; Andersen, Jens V.

doi:10.1007/s12035-022-03053-5

Cited by 12 publications

(6 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This was also observed for direct synthesis of glutamine (−27.6%, p = 0.014) and GABA (−24.2%, p = 0.033) from [U‐ 13 C]glutamate metabolism. After direct metabolism of [U‐ 13 C]glutamate, the glutamate carbon skeleton can cycle through the TCA cycle again, leading to M + 2 and M + 3 enrichments of TCA cycle intermediates and amino acids (first turn metabolism) (Westi et al, 2022). First turn metabolism of [U‐ 13 C]glutamate was also reduced in all measured metabolites (α‐ketoglutarate M + 3: −27.7%, p = 0.010; fumarate M + 3: −33.1%, p = 0.003; malate M + 2: −24.6%, p = 0.021; citrate M + 2: −25.4%, p = 0.013; aspartate M + 2: −24.2%, p = 0.012; glutamate M + 3: −19.1%, p = 0.017; glutamine M + 3: −19.8%; p = 0.027, GABA M + 2: −20.5%, p = 0.027).…”

Section: Resultsmentioning

confidence: 99%

Deletion of CaMKIIα disrupts glucose metabolism, glutamate uptake, and synaptic energetics in the cerebral cortex

Andersen

Westi

Griem-Krey

et al. 2023

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

Ca2+/calmodulin‐dependent protein kinase II alpha (CaMKIIα) is a key regulator of neuronal signaling and synaptic plasticity. Synaptic activity and neurotransmitter homeostasis are closely coupled to the energy metabolism of both neurons and astrocytes. However, whether CaMKIIα function is implicated in brain energy and neurotransmitter metabolism remains unclear. Here, we explored the metabolic consequences of CaMKIIα deletion in the cerebral cortex using a genetic CaMKIIα knockout (KO) mouse. Energy and neurotransmitter metabolism was functionally investigated in acutely isolated cerebral cortical slices using stable 13C isotope tracing, whereas the metabolic function of synaptosomes was assessed by the rates of glycolytic activity and mitochondrial respiration. The oxidative metabolism of [U‐13C]glucose was extensively reduced in cerebral cortical slices of the CaMKIIα KO mice. In contrast, metabolism of [1,2‐13C]acetate, primarily reflecting astrocyte metabolism, was unaffected. Cellular uptake, and subsequent metabolism, of [U‐13C]glutamate was decreased in cerebral cortical slices of CaMKIIα KO mice, whereas uptake and metabolism of [U‐13C]GABA were unaffected, suggesting selective metabolic impairments of the excitatory system. Synaptic metabolic function was maintained during resting conditions in isolated synaptosomes from CaMKIIα KO mice, but both the glycolytic and mitochondrial capacities became insufficient when the synaptosomes were metabolically challenged. Collectively, this study shows that global deletion of CaMKIIα significantly impairs cellular energy and neurotransmitter metabolism, particularly of neurons, suggesting a metabolic role of CaMKIIα signaling in the brain.image

show abstract

Section: Resultsmentioning

confidence: 99%

Deletion of CaMKIIα disrupts glucose metabolism, glutamate uptake, and synaptic energetics in the cerebral cortex

Andersen

Westi

Griem-Krey

et al. 2023

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Metabolism Of Glutamate and Gabamentioning

confidence: 99%

“…Recently, species‐specific differences in glutamate metabolism were explored in acutely isolated cerebral cortical slices of mice and humans (Westi et al, 2022). Overall, the direct metabolism of exogenous [U‐ 13 C]glutamate was preserved between the mouse and human cerebral cortex, however, human brain slices exhibited higher synthesis of glutamine, and subsequent GABA formation, from metabolism of [U‐ 13 C]glutamate (Westi et al, 2022). Since glutamine is synthesized in astrocytes, these results suggest that human astrocytes exhibits a higher capacity for glutamine synthesis, hereby supporting neuronal GABA replenishment as part of the glutamine‐GABA cycle (Figure 2).…”

Section: Metabolism Of Glutamate and Gabamentioning

confidence: 99%

“…Since glutamine is synthesized in astrocytes, these results suggest that human astrocytes exhibits a higher capacity for glutamine synthesis, hereby supporting neuronal GABA replenishment as part of the glutamine‐GABA cycle (Figure 2). Furthermore, incubation with [U‐ 13 C]glutamate resulted in a selective increase of the intracellular aspartate content in brain slices of mice (Westi et al, 2022), suggesting that AAT activity may be the dominant pathway of handling elevated exogenous glutamate levels in rodents. This agrees well with the expression profile of AAT (genes: Got1 and Got2 ), which are particularly enriched in the rodent brain compared with human (Sjöstedt et al, 2020).…”

Section: Metabolism Of Glutamate and Gabamentioning

confidence: 99%

See 1 more Smart Citation

Milestone Review: Metabolic dynamics of glutamate and GABA mediated neurotransmission — The essential roles of astrocytes

Andersen

Schousboe

2023

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

Since it was first generally accepted that the two amino acids glutamate and GABA act as principal neurotransmitters, several landmark discoveries relating to this function have been uncovered. Synaptic homeostasis of these two transmitters involves several cell types working in close collaboration and is facilitated by specialized cellular processes. Notably, glutamate and GABA are extensively recycled between neurons and astrocytes in a process known as the glutamate/GABA-glutamine cycle, which is essential to maintain synaptic transmission. The glutamate/GABAglutamine cycle is intimately coupled to cellular energy metabolism and relies on the metabolic function of both neurons and astrocytes. Importantly, astrocytes display unique metabolic features allowing extensive metabolite release, hereby providing metabolic support for neurons. Furthermore, astrocytes undergo complex metabolic adaptations in response to injury and pathology, which may greatly affect the glutamate/GABA-glutamine cycle and synaptic transmission during disease. In this Milestone Review we outline major discoveries in relation to synaptic balancing of glutamate and GABA signaling, including cellular uptake, metabolism, and recycling.We provide a special focus on how astrocyte function and metabolism contribute to sustain neuronal transmission through metabolite transfer. Recent advances on cellular glutamate and GABA homeostasis are reviewed in the context of brain pathology, including glutamate toxicity and neurodegeneration. Finally, we consider how pathological astrocyte metabolism may serve as a potential target of metabolic intervention. Integrating the multitude of fine-tuned cellular processes supporting neurotransmitter recycling, will aid the next generation of major discoveries on brain glutamate and GABA homeostasis.

show abstract

“…White matter degeneration in AD could be in part due to the accelerated degradation of lipids in this context of decreased energetic metabolism coming from reduced glucose utilization (Fig. 2 ) [ 141 , 206 ].…”

Section: Multiple Causes Multiple Targetsmentioning

confidence: 99%

Myelin in Alzheimer’s disease: culprit or bystander?

Maître

Jeltsch-David

Okechukwu

et al. 2023

acta neuropathol commun

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a neurodegenerative disorder with neuronal and synaptic losses due to the accumulation of toxic amyloid β (Αβ) peptide oligomers, plaques, and tangles containing tau (tubulin-associated unit) protein. While familial AD is caused by specific mutations, the sporadic disease is more common and appears to result from a complex chronic brain neuroinflammation with mitochondriopathies, inducing free radicals’ accumulation. In aged brain, mutations in DNA and several unfolded proteins participate in a chronic amyloidosis response with a toxic effect on myelin sheath and axons, leading to cognitive deficits and dementia. Αβ peptides are the most frequent form of toxic amyloid oligomers. Accumulations of misfolded proteins during several years alters different metabolic mechanisms, induce chronic inflammatory and immune responses with toxic consequences on neuronal cells. Myelin composition and architecture may appear to be an early target for the toxic activity of Aβ peptides and others hydrophobic misfolded proteins. In this work, we describe the possible role of early myelin alterations in the genesis of neuronal alterations and the onset of symptomatology. We propose that some pathophysiological and clinical forms of the disease may arise from structural and metabolic disorders in the processes of myelination/demyelination of brain regions where the accumulation of non-functional toxic proteins is important. In these forms, the primacy of the deleterious role of amyloid peptides would be a matter of questioning and the initiating role of neuropathology would be primarily the fact of dysmyelination.

show abstract

Divergent Cellular Energetics, Glutamate Metabolism, and Mitochondrial Function Between Human and Mouse Cerebral Cortex

Cited by 12 publications

References 91 publications

Deletion of CaMKIIα disrupts glucose metabolism, glutamate uptake, and synaptic energetics in the cerebral cortex

Deletion of CaMKIIα disrupts glucose metabolism, glutamate uptake, and synaptic energetics in the cerebral cortex

Milestone Review: Metabolic dynamics of glutamate and GABA mediated neurotransmission — The essential roles of astrocytes

Myelin in Alzheimer’s disease: culprit or bystander?

Contact Info

Product

Resources

About