The Response to Stimulation in Neurons and Astrocytes

Juaristi, Inés; Contreras, Laura; González-Sánchez, Paloma; Pérez-Liébana, Irene; González-Moreno, Luis; Pardo, Beatriz; Arco, Araceli del; Satrústegui, Jorgina

doi:10.1007/s11064-019-02803-7

Cited by 27 publications

(21 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Downregulated glycolytic response to mitochondrial stress was also confirmed in human iPSC-derived astrocytes with PS1-ΔE9 mutations 39 . Astrocytes have significantly higher glycolytic metabolism than neurons through which they feed neurons, store glycogen and metabolize and recycle neurotransmitters 40 , 41 . Slowing down astrocytic glycolysis may have detrimental effects on neuronal activity and survival.…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis links alterations of bioenergetics, mitochondria-ER interactions and proteostasis in hippocampal astrocytes from 3xTg-AD mice

et al. 2020

View full text Add to dashboard Cite

The pathogenesis of Alzheimer's disease (AD), a slowly-developing age-related neurodegenerative disorder, is a result of the action of multiple factors including deregulation of Ca 2+ homeostasis, mitochondrial dysfunction, and dysproteostasis. Interaction of these factors in astrocytes, principal homeostatic cells in the central nervous system, is still poorly understood. Here we report that in immortalized hippocampal astrocytes from 3xTg-AD mice (3Tg-iAstro cells) bioenergetics is impaired, including reduced glycolysis and mitochondrial oxygen consumption, and increased production of reactive oxygen species. Shotgun proteomics analysis of mitochondria-ER-enriched fraction showed no alterations in the expression of mitochondrial and OxPhos proteins, while those related to the ER functions and protein synthesis were deregulated. Using ER-and mitochondria-targeted aequorin-based Ca 2+ probe we show that, in 3Tg-iAstro cells, ER was overloaded with Ca 2+ while Ca 2+ uptake by mitochondria upon ATP stimulation was reduced. This was accompanied by the increase in short distance (≈8-10 nm) contact area between mitochondria and ER, upregulation of ER-stress/unfolded protein response genes Atf4, Atf6 and Herp, and reduction of global protein synthesis rate. We suggest that familial AD mutations in 3Tg-iAstro cells induce mitochondria-ER interaction changes that deregulate astrocytic bioenergetics, Ca 2+ homeostasis and proteostasis. These factors may interact, creating a pathogenic loop compromising homeostatic and defensive functions of astroglial cells predisposing neurons to dysfunction.

show abstract

Section: Discussionmentioning

confidence: 99%

Proteomic analysis links alterations of bioenergetics, mitochondria-ER interactions and proteostasis in hippocampal astrocytes from 3xTg-AD mice

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The most striking departure from the simple picture described above is the apparent mismatch of the rates of different processes. The CMRGlc change with increasing neural activity is much larger than the CMRO 2 change [8,[13][14][15], and some of the excess pyruvate created is converted to lactate [15,16]. The production of lactate is surprising given that there appears to be no lack of available oxygen, and this phenomenon has been called 'aerobic , and ATP is consumed in recovery from that activity, primarily in restoring ion gradients.…”

Section: Introduction: the Challenge Of Interpreting Metabolism And Bmentioning

confidence: 99%

The thermodynamics of thinking: connections between neural activity, energy metabolism and blood flow

Buxton

2020

Phil. Trans. R. Soc. B

View full text Add to dashboard Cite

Several current functional neuroimaging methods are sensitive to cerebral metabolism and cerebral blood flow (CBF) rather than the underlying neural activity itself. Empirically, the connections between metabolism, flow and neural activity are complex and somewhat counterintuitive: CBF and glycolysis increase more than seems to be needed to provide oxygen and pyruvate for oxidative metabolism, and the oxygen extraction fraction is relatively low in the brain and decreases when oxygen metabolism increases. This work lays a foundation for the idea that this unexpected pattern of physiological changes is consistent with basic thermodynamic considerations related to metabolism. In the context of this thermodynamic framework, the apparent mismatches in metabolic rates and CBF are related to preserving the entropy change of oxidative metabolism, specifically the O 2 /CO 2 ratio in the mitochondria. However, the mechanism supporting this CBF response is likely not owing to feedback from a hypothetical O 2 sensor in tissue, but rather is consistent with feed-forward control by signals from both excitatory and inhibitory neural activity. Quantitative predictions of the thermodynamic framework, based on models of O 2 and CO 2 transport and possible neural drivers of CBF control, are in good agreement with a wide range of experimental data, including responses to neural activation, hypercapnia, hypoxia and high-altitude acclimatization. This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity’.

show abstract

“…These results show that lactate arises from neuronal synthesis rather than by capture from the external media, as shown in activated brain neurons (Díaz-García et al, 2017). It should be noted that neuronal cultures have a relatively large lactate production even in the basal state (Juaristi et al, 2019a, b), possibly larger than that of brain neurons, likely limited by astrocyte lactate buildup in the extracellular space. However, regardless of the actual basal state, NMDA clearly stimulates lactate production even in the presence of 2 mM lactate in the media (Fig.…”

Section: Resultsmentioning

confidence: 99%

“A feed-forward Ca²⁺-dependent mechanism boosting glycolysis and OXPHOS by activating Aralar-malate-aspartate shuttle, upon neuronal stimulation”

Pérez-Liébana

Juaristi

González-Sánchez

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Calcium is an important second messenger regulating a bioenergetic response to the workloads triggered by neuronal activation. In cortical neurons using glucose as only fuel, activation by NMDA, which elicits a strong workload dependent on Na+ entry, stimulates glucose uptake, glycolysis, pyruvate and lactate production, and OXPHOS in a Ca2+-dependent way. We find that Ca2+-upregulation of glycolysis, pyruvate levels and respiration, but not glucose uptake, all depend on Aralar/AGC1/Slc25a12, the Ca2+regulated mitochondrial aspartate-glutamate carrier, component of the malate-aspartate shuttle (MAS). Ca2+-activation of MAS increases pyruvate production, which directly fuels workload-stimulated respiration. Also it stimulates glycolysis. MCU silencing had no effect indicating that none of these processes required mitochondrial Ca2+. The neuronal respiratory response to carbachol was also dependent on Aralar, but not on MCU. We also find that cortical neurons are endowed with a constitutive ER-to-mitochondria Ca2+ flow maintaining basal cell bioenergetics in which Ryanodine receptors, RyR2, rather than InsP3R, are responsible for Ca2+ release, and in which MCU does not participate. The results reveal that in neurons using glucose MCU does not participate in OXPHOS regulation under basal or stimulated conditions, while Aralar-MAS appears as the major Ca2+-dependent pathway tuning simultaneously glycolysis and OXPHOS to neuronal activation.

show abstract

The Response to Stimulation in Neurons and Astrocytes

Cited by 27 publications

References 67 publications

Proteomic analysis links alterations of bioenergetics, mitochondria-ER interactions and proteostasis in hippocampal astrocytes from 3xTg-AD mice

Proteomic analysis links alterations of bioenergetics, mitochondria-ER interactions and proteostasis in hippocampal astrocytes from 3xTg-AD mice

The thermodynamics of thinking: connections between neural activity, energy metabolism and blood flow

“A feed-forward Ca²⁺-dependent mechanism boosting glycolysis and OXPHOS by activating Aralar-malate-aspartate shuttle, upon neuronal stimulation”

Contact Info

Product

Resources

About

The Response to Stimulation in Neurons and Astrocytes

Cited by 27 publications

References 67 publications

Proteomic analysis links alterations of bioenergetics, mitochondria-ER interactions and proteostasis in hippocampal astrocytes from 3xTg-AD mice

Proteomic analysis links alterations of bioenergetics, mitochondria-ER interactions and proteostasis in hippocampal astrocytes from 3xTg-AD mice

The thermodynamics of thinking: connections between neural activity, energy metabolism and blood flow

“A feed-forward Ca2+-dependent mechanism boosting glycolysis and OXPHOS by activating Aralar-malate-aspartate shuttle, upon neuronal stimulation”

Contact Info

Product

Resources

About

“A feed-forward Ca²⁺-dependent mechanism boosting glycolysis and OXPHOS by activating Aralar-malate-aspartate shuttle, upon neuronal stimulation”