Astrocyte–neuron metabolic relationships: for better and for worse

Allaman, Igor; Bélanger, Marcel; Magistretti, Pierre J.

doi:10.1016/j.tins.2010.12.001

Cited by 551 publications

(461 citation statements)

References 132 publications

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“…This is consistent with the dependence of neurons on oxidative phosphorylation for neurotransmission and survival (17)(18)(19). In contrast, the smaller proportion of complex I that is assembled into supercomplexes in astrocytes may contribute to their lower respiration rate and is consistent with their more glycolytic metabolism (17)(18)(19)(20)(21)(22). A further intriguing aspect is that the large difference in mitochondrial ROS production between neurons and astrocytes correlates with the amount of free complex I.…”

Section: Discussionsupporting

confidence: 72%

“…In fact, the survival of neurons requires oxidative phosphorylation (18,19). The different energy metabolisms of the two cell types are closely coupled, with astrocytes releasing the glycolytic end product, lactate, which is used by neighboring neurons to drive oxidative phosphorylation (20)(21)(22). As the molecular mechanisms underlying the markedly different modes of ATP production in the two cell types are not understood, we investigated whether the organization of the mitochondrial respiratory chain in brain cells could contribute.…”

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confidence: 99%

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Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes

López-Fabuel

Douce

Logan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

322

278

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Neurons depend on oxidative phosphorylation for energy generation, whereas astrocytes do not, a distinctive feature that is essential for neurotransmission and neuronal survival. However, any link between these metabolic differences and the structural organization of the mitochondrial respiratory chain is unknown. Here, we investigated this issue and found that, in neurons, mitochondrial complex I is predominantly assembled into supercomplexes, whereas in astrocytes the abundance of free complex I is higher. The presence of free complex I in astrocytes correlates with the severalfold higher reactive oxygen species (ROS) production by astrocytes compared with neurons. Using a complexomics approach, we found that the complex I subunit NDUFS1 was more abundant in neurons than in astrocytes. Interestingly, NDUFS1 knockdown in neurons decreased the association of complex I into supercomplexes, leading to impaired oxygen consumption and increased mitochondrial ROS. Conversely, overexpression of NDUFS1 in astrocytes promoted complex I incorporation into supercomplexes, decreasing ROS. Thus, complex I assembly into supercomplexes regulates ROS production and may contribute to the bioenergetic differences between neurons and astrocytes.redox | brain | bioenergetics | lactate | glycolysis T he brain is a metabolically demanding organ (1) that requires tight cooperation between neurons and astrocytes (2). Astrocytes provide crucial metabolic and structural support (3, 4) and are key players in neurotransmission (5-7) and behavior (8). The status of many major redox couples in the brain is also regulated by astrocytes (9), through their high content of antioxidant compounds and enzymes (10) and by the constitutive stabilization of the master antioxidant transcriptional activator, nuclear factor erythroid 2-related factor 2 (Nrf2) (11). Thus, astrocytes are equipped to protect themselves when exposed to excess reactive oxygen species (ROS) (12) and reactive nitrogen species (13,14). Moreover, astrocytes also provide nearby neurons with protective antioxidant precursors through a cell-signaling mechanism involving glutamate receptor activation by neurotransmission (11,15,16). The tight coupling between astrocytes and neurons therefore helps in energy and redox metabolism during normal brain function.Intriguingly, the ATP used by neurons is supplied by oxidative phosphorylation, whereas most energy needs of astrocytes are met by glycolysis (17). In fact, the survival of neurons requires oxidative phosphorylation (18,19). The different energy metabolisms of the two cell types are closely coupled, with astrocytes releasing the glycolytic end product, lactate, which is used by neighboring neurons to drive oxidative phosphorylation (20)(21)(22). As the molecular mechanisms underlying the markedly different modes of ATP production in the two cell types are not understood, we investigated whether the organization of the mitochondrial respiratory chain in brain cells could contribute. Here, we report that the extent of supercomplex f...

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Section: Discussionsupporting

confidence: 72%

mentioning

confidence: 99%

Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes

López-Fabuel

Douce

Logan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

322

278

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“…One possibility is that OX inhibition increases neural excitability, perhaps by shifting cells to a more excitable reduced redox state (44), or shifting metabolic flux toward increased glycolysis in either the neurons or the metabolically coupled glia (43,(45)(46)(47)(48), leading to faster ATP production or glutamate turnover at synapses (10, 13, 49) and increased firing potential (50). Increased neural excitability could allow individuals to respond more quickly to aggressive stimuli, and neural excitability above typical levels has been associated with mood disorders and increased aggression in humans (51).…”

Section: Discussionmentioning

confidence: 99%

Socially responsive effects of brain oxidative metabolism on aggression

Li-Byarlay

Rittschof

Massey

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

108

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Despite ongoing high energetic demands, brains do not always use glucose and oxygen in a ratio that produces maximal ATP through oxidative phosphorylation. In some cases glucose consumption exceeds oxygen use despite adequate oxygen availability, a phenomenon known as aerobic glycolysis. Although metabolic plasticity seems essential for normal cognition, studying its functional significance has been challenging because few experimental systems link brain metabolic patterns to distinct behavioral states. Our recent transcriptomic analysis established a correlation between aggression and decreased whole-brain oxidative phosphorylation activity in the honey bee (Apis mellifera), suggesting that brain metabolic plasticity may modulate this naturally occurring behavior. Here we demonstrate that the relationship between brain metabolism and aggression is causal, conserved over evolutionary time, cell type-specific, and modulated by the social environment. Pharmacologically treating honey bees to inhibit complexes I or V in the oxidative phosphorylation pathway resulted in increased aggression. In addition, transgenic RNAi lines and genetic manipulation to knock down gene expression in complex I in fruit fly (Drosophila melanogaster) neurons resulted in increased aggression, but knockdown in glia had no effect. Finally, honey bee colony-level social manipulations that decrease individual aggression attenuated the effects of oxidative phosphorylation inhibition on aggression, demonstrating a specific effect of the social environment on brain function. Because decreased neuronal oxidative phosphorylation is usually associated with brain disease, these findings provide a powerful context for understanding brain metabolic plasticity and naturally occurring behavioral plasticity.M etabolic dynamics are critical to brain function in both vertebrate and invertebrate species (1-3). In mammals, cognitive and behavioral tasks result in increased glucose metabolism and minor increases in oxygen consumption (relative to availability), and similar processes have been shown to occur in insects (3, 4). These metabolic changes underlie widely used technologies that measure brain activity (e.g., functional MRI and PET) (5-7). Because the brain is an energetically demanding organ with high ATP requirements (8), temporal and spatial variation in glucose metabolism is generally assumed to fulfill the energetic demands of signaling and recovery (5). Paradoxically, in humans, less than 10% of the glucose that is taken up as a result of brain activity is fully oxidized through oxidative phosphorylation (OX) to produce ATP, despite adequate oxygen availability, a phenomenon known as aerobic glycolysis (6, 9-11). Furthermore total glucose uptake by the adult human brain exceeds oxygen use by 10-12% (12). Thus, increased demand for high levels of ATP is inadequate to explain the function of variation in glucose metabolism in the brain. Understanding the functional significance of metabolic plasticity, which is essential for cognition but also l...

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“…Although most research has focused on the effect of Tau protein tangles and A␤ plaques on neuronal function and survival, it is now well established that astrocytes also play a role in AD pathology (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). In the CNS, astrocytes are indispensable for the support of neurons.…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

Astrocytes Secrete Exosomes Enriched with Proapoptotic Ceramide and Prostate Apoptosis Response 4 (PAR-4)

Wang¹,

Dinkins²,

He³

et al. 2012

Journal of Biological Chemistry

327

305

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Background:In AD, amyloid protein is associated with neurodegeneration, which may involve amyloid effects on astrocytes. Results: In astrocytes, amyloid peptide triggers secretion of proapoptotic exosomes ("apoxosomes") that are associated with ceramide and PAR-4. Conclusion: Activation of nSMase2 and expression of PAR-4 is critical for the secretion of apoxosomes and glial apoptosis. Significance: Apoxosomes may contribute to glial apoptosis, and therefore, neurodegeneration in AD.Amyloid protein is well known to induce neuronal cell death, whereas only little is known about its effect on astrocytes. We found that amyloid peptides activated caspase 3 and induced apoptosis in primary cultured astrocytes, which was prevented by caspase 3 inhibition. Apoptosis was also prevented by shRNA-mediated down-regulation of PAR-4, a protein sensitizing cells to the sphingolipid ceramide. Consistent with a potentially proapoptotic effect of PAR-4 and ceramide, astrocytes surrounding amyloid plaques in brain sections of the 5xFAD mouse (and Alzheimer disease patient brain) showed caspase 3 activation and were apoptotic when co-expressing PAR-4 and ceramide. Apoptosis was not observed in astrocytes with deficient neutral sphingomyelinase 2 (nSMase2), indicating that ceramide generated by nSMase2 is critical for amyloid-induced apoptosis. Antibodies against PAR-4 and ceramide prevented amyloid-induced apoptosis in vitro and in vivo, suggesting that apoptosis was mediated by exogenous PAR-4 and ceramide, potentially associated with secreted lipid vesicles. This was confirmed by the analysis of lipid vesicles from conditioned medium showing that amyloid peptide induced the secretion of PAR-4 and C18 ceramide-enriched exosomes. Exosomes were not secreted by nSMase2-deficient astrocytes, indicating that ceramide generated by nSMase2 is critical for exosome secretion. Consistent with the ceramide composition in amyloid-induced exosomes, exogenously added C18 ceramide restored PAR-4-containing exosome secretion in nSMase2-deficient astrocytes. Moreover, isolated PAR-4/ceramide-enriched exosomes were taken up by astrocytes and induced apoptosis in the absence of amyloid peptide. Taken together, we report a novel mechanism of apoptosis induction by PAR-4/ceramide-enriched exosomes, which may critically contribute to Alzheimer disease.

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Astrocyte–neuron metabolic relationships: for better and for worse

Cited by 551 publications

References 132 publications

Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes

Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes

Socially responsive effects of brain oxidative metabolism on aggression

Astrocytes Secrete Exosomes Enriched with Proapoptotic Ceramide and Prostate Apoptosis Response 4 (PAR-4)

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