Brain Energy Metabolism: Astrocytes in Neurodegenerative Diseases

Chen, Zhenlei; Yuan, Ziqi; Yang, Shangchen; Zhu, Yong; Xue, Mei; Zhang, Jie; Leng, Lige

doi:10.1111/cns.13982

Cited by 38 publications

(23 citation statements)

References 141 publications

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“…Glucose is considered as the main physiological substrate of astrocytes [ 8 ]. However, at least in culture these cells are able to also utilize a substantial number of other substrates that can be oxidized to provide energy via mitochondrial processes, including pyruvate, lactate, acetate, ketone bodies as well as amino acids and fatty acids [ 1 , 5 , 21 – 25 ].…”

Section: Introductionmentioning

confidence: 99%

Endogenous Energy Stores Maintain a High ATP Concentration for Hours in Glucose-Depleted Cultured Primary Rat Astrocytes

et al. 2023

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Adenosine triphosphate (ATP) is the central energy currency of all cells. Cultured primary rat astrocytes contain a specific cellular ATP content of 27.9 ± 4.7 nmol/mg. During incubation in a glucose- and amino acid-free incubation buffer, this high cellular ATP content was maintained for at least 6 h, while within 24 h the levels of ATP declined to around 30% of the initial value without compromising cell viability. In contrast, cells exposed to 1 mM and 5 mM glucose maintained the initial high cellular ATP content for 24 and 72 h, respectively. The loss in cellular ATP content observed during a 24 h glucose-deprivation was fully prevented by the presence of glucose, fructose or mannose as well as by the mitochondrial substrates lactate, pyruvate, β-hydroxybutyrate or acetate. The high initial specific ATP content in glucose-starved astrocytes, was almost completely abolished within 30 min after application of the respiratory chain inhibitor antimycin A or the mitochondrial uncoupler BAM-15, while these inhibitors lowered in glucose-fed cells the ATP content only to 60% (BAM-15) and 40% (antimycin A) within 5 h. Inhibition of the mitochondrial pyruvate carrier by UK5099 alone or of mitochondrial fatty acid uptake by etomoxir alone hardly affected the high ATP content of glucose-deprived astrocytes during an incubation for 8 h, while the co-application of both inhibitors depleted cellular ATP levels almost completely within 5 h. These data underline the importance of mitochondrial metabolism for the ATP regeneration of astrocytes and demonstrate that the mitochondrial oxidation of pyruvate and fatty acids strongly contributes to the maintenance of a high ATP concentration in glucose-deprived astrocytes.

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Section: Introductionmentioning

confidence: 99%

Endogenous Energy Stores Maintain a High ATP Concentration for Hours in Glucose-Depleted Cultured Primary Rat Astrocytes

et al. 2023

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“…In order to identify, in the most effective way, precise therapeutic targets in the mitochondrial compartment, it would be useful to evaluate the morphological and functional changes of every cellular type that, other than neurons, interacts in the central nervous system, namely astrocytes, oligodendrocytes, pericytes and microglial cells, all contributing to the brain homeostasis. The role of the so-called neurovascular unit [ 163 , 164 ] has been fully recognized in the evaluation of the pathogenesis of neurodegenerative diseases ( Figure 2 ). Nevertheless, at the moment, we still need to clarify its contribution as a pharmacological target in regard to mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Mitochondria-Targeted Antioxidants, an Innovative Class of Antioxidant Compounds for Neurodegenerative Diseases: Perspectives and Limitations

Fields

Marcuzzi

Gonelli

et al. 2023

IJMS

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Neurodegenerative diseases comprise a wide spectrum of pathologies characterized by progressive loss of neuronal functions and structures. Despite having different genetic backgrounds and etiology, in recent years, many studies have highlighted a point of convergence in the mechanisms leading to neurodegeneration: mitochondrial dysfunction and oxidative stress have been observed in different pathologies, and their detrimental effects on neurons contribute to the exacerbation of the pathological phenotype at various degrees. In this context, increasing relevance has been acquired by antioxidant therapies, with the purpose of restoring mitochondrial functions in order to revert the neuronal damage. However, conventional antioxidants were not able to specifically accumulate in diseased mitochondria, often eliciting harmful effects on the whole body. In the last decades, novel, precise, mitochondria-targeted antioxidant (MTA) compounds have been developed and studied, both in vitro and in vivo, to address the need to counter the oxidative stress in mitochondria and restore the energy supply and membrane potentials in neurons. In this review, we focus on the activity and therapeutic perspectives of MitoQ, SkQ1, MitoVitE and MitoTEMPO, the most studied compounds belonging to the class of MTA conjugated to lipophilic cations, in order to reach the mitochondrial compartment.

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“…Secondly, our model does not fully consider the factors affecting astrocyte Ca 2+ dynamics. In astrocytes, in addition to glutamate, ATP, GABA and other signaling pathways also affect Ca 2+ signalization and contribute to the regulation of a number of both physiological and pathophysiological processes in the nervous system as well (Chen et al, 2023). The model only examined a subset of the astrocyte microdomains and did not take into account the extracellular Ca 2+ diffusion.…”

Section: The Impactmentioning

confidence: 99%

Probing microdomain Ca2+ activity and synaptic transmission with a node-based tripartite synapse model

Liu

Gao

et al. 2023

Front. Netw. Physiol.

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Astrocytic fine processes are the most minor structures of astrocytes but host much of the Ca2+ activity. These localized Ca2+ signals spatially restricted to microdomains are crucial for information processing and synaptic transmission. However, the mechanistic link between astrocytic nanoscale processes and microdomain Ca2+ activity remains hazily understood because of the technical difficulties in accessing this structurally unresolved region. In this study, we used computational models to disentangle the intricate relations of morphology and local Ca2+ dynamics involved in astrocytic fine processes. We aimed to answer: 1) how nano-morphology affects local Ca2+ activity and synaptic transmission, 2) and how fine processes affect Ca2+ activity of large process they connect. To address these issues, we undertook the following two computational modeling: 1) we integrated the in vivo astrocyte morphological data from a recent study performed with super-resolution microscopy that discriminates sub-compartments of various shapes, referred to as nodes and shafts to a classic IP3R-mediated Ca2+ signaling framework describing the intracellular Ca2+ dynamics, 2) we proposed a node-based tripartite synapse model linking with astrocytic morphology to predict the effect of structural deficits of astrocytes on synaptic transmission. Extensive simulations provided us with several biological insights: 1) the width of nodes and shafts could strongly influence the spatiotemporal variability of Ca2+ signals properties but what indeed determined the Ca2+ activity was the width ratio between nodes and shafts, 2) the connectivity of nodes to larger processes markedly shaped the Ca2+ signal of the parent process rather than nodes morphology itself, 3) the morphological changes of astrocytic part might potentially induce the abnormality of synaptic transmission by affecting the level of glutamate at tripartite synapses. Taken together, this comprehensive model which integrated theoretical computation and in vivo morphological data highlights the role of the nanomorphology of astrocytes in signal transmission and its possible mechanisms related to pathological conditions.

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Brain Energy Metabolism: Astrocytes in Neurodegenerative Diseases

Cited by 38 publications

References 141 publications

Endogenous Energy Stores Maintain a High ATP Concentration for Hours in Glucose-Depleted Cultured Primary Rat Astrocytes

Endogenous Energy Stores Maintain a High ATP Concentration for Hours in Glucose-Depleted Cultured Primary Rat Astrocytes

Mitochondria-Targeted Antioxidants, an Innovative Class of Antioxidant Compounds for Neurodegenerative Diseases: Perspectives and Limitations

Probing microdomain Ca2+ activity and synaptic transmission with a node-based tripartite synapse model

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