Monocarboxylate transporter 1 and the vulnerability of oligodendrocyte lineage cells to metabolic stresses

Zhou, Peng; Guan, Teng; Jiang, Zhaoyan; Namaka, Michael; Huang, Qingjun; Kong, Jiming

doi:10.1111/cns.12782

Cited by 26 publications

(29 citation statements)

References 18 publications

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“…Here, we used the laser-induced ischemic mouse model to examine the underlying reasons behind sustained expressions of iNOS and MCT1 in damaged rodent brains. Previously, increase in MCT1 expression was reported after ischemia in mice [47,48]. We demonstrated that microglia produced greater iNOS + and MCT1 under low glucose condition.…”

Section: Discussionsupporting

confidence: 56%

Pyruvate enhances M1 microglial polarization via NF-κB/MCT1/iNOS signaling axis under low glucose condition

Zhou

et al. 2020

Preprint

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Background Proinflammatory microglia rely predominantly on glycolysis to maintain cytokine production during an inflammatory response. However, during ischemia, where glucose supply is low, inducible nitric oxide synthase (iNOS) production remains high accompanied by an increase in monocarboxylate transporter 1 (MCT1) expression. In this study, we explored whether there is a link between iNOS and MCT1 expressions, and whether pyruvate can act as an energy source to sustain the M1 phenotype. Methods Using a mouse model with laser-induced brain ischemia and cell culture with low-glucose treatment, we examined responses from microglia. Results The expressions of iNOS and MCT1, as well as arginase-1 (ARG1), were increased in the brain of the ischemic mouse model. In the BV2 microglial cell line and primary microglia treated under low glucose condition, iNOS and MCT1 also increased, while ARG1 decreased. The addition of pyruvate under low-glucose or lipopolysaccharide (LPS) treatment enhanced iNOS and MCT1 expressions compared with groups without pyruvate. MCT1 knockdown resulted in decreased iNOS while MCT1 overexpression increased iNOS. Furthermore, inhibitor of nuclear factor-kappaB (NF-κB) reduced both iNOS and MCT1. Conclusion Our data suggested that after proinflammatory microglial polarization, MCT1 is upregulated through the NF-κB signaling pathway, which leads to iNOS production. We speculate that microglia may continuously pick up monocarboxylates such as pyruvate through MCT1 to sustain the M1 phenotype.

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Section: Discussionsupporting

confidence: 56%

Pyruvate enhances M1 microglial polarization via NF-κB/MCT1/iNOS signaling axis under low glucose condition

Zhou

et al. 2020

Preprint

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“…Oligodendrocyte function depends on glucose concentrations since hypoglycemia inhibits myelin development (Yan and Rivkees 2006). In fact, oxygen starvation and glucose deprivation are the two main metabolic stressors linked to neurodegeneration (Zhou and others 2018). On glucose deprivation, OPCs have fewer and thinner processes while oligodendrocytes show little change in branching morphology under stress (Zhou and others 2018), suggesting that OPCs, which have high mitochondrial demands, are highly susceptible to metabolic stress injury.…”

Section: Glucose Fuels Oligodendrocyte Survival and Promotes Myelinationmentioning

confidence: 99%

“…In fact, oxygen starvation and glucose deprivation are the two main metabolic stressors linked to neurodegeneration (Zhou and others 2018). On glucose deprivation, OPCs have fewer and thinner processes while oligodendrocytes show little change in branching morphology under stress (Zhou and others 2018), suggesting that OPCs, which have high mitochondrial demands, are highly susceptible to metabolic stress injury. Moreover, although oligodendrocytes do not display morphological changes under an acute stress condition, metabolic stress has been shown to cause oligodendrocytes to shift to a predominately glycolytic metabolism in favor of survival rather than the maintenance of myelin membranes (Rone and others 2016).…”

Section: Glucose Fuels Oligodendrocyte Survival and Promotes Myelinationmentioning

confidence: 99%

“…Several studies have shown that disruption of oligodendrocyte-axon coupling may contribute to disease pathogenesis. After ischemic injury in the CNS, striatum levels of MCT1 are significantly upregulated in animals following reperfusion of the middle cerebral artery (Zhou and others 2018). Oxygen-glucose deprivation from ischemia triggers the upregulation of MCT1 in OPCs to allow increased transport of lactate from astrocytes and from the blood.…”

Section: Lactate Promotes Oligodendrocyte-axon Couplingmentioning

confidence: 99%

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Oligodendrocyte Bioenergetics in Health and Disease

et al. 2018

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The human brain weighs approximately 2% of the body; however, it consumes about 20% of a person's total energy intake. Cellular bioenergetics in the central nervous system involves a delicate balance between biochemical processes engaged in energy conversion and those responsible for respiration. Neurons have high energy demands, which rely on metabolic coupling with glia, such as with oligodendrocytes and astrocytes. It has been well established that astrocytes recycle and transport glutamine to neurons to make the essential neurotransmitters, glutamate and GABA, as well as shuttle lactate to support energy synthesis in neurons. However, the metabolic role of oligodendrocytes in the central nervous system is less clear. In this review, we discuss the energetic demands of oligodendrocytes in their survival and maturation, the impact of altered oligodendrocyte energetics on disease pathology, and the role of energetic metabolites, taurine, creatine, N-acetylaspartate, and biotin, in regulating oligodendrocyte function.

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“…Unlike astrocytes, oligodendrocytes cannot withstand energy deprivation for long time period; in fact, morphological changes of oligodendrocytes have been observed within 30 min after MCAO, and chromatin changes within 6 h (Pantoni et al, 1996). Oligodendrocyte progenitor cells (OPC) and oligodendrocytes show morphological changes under conditions of compromised metabolism (Zhou et al, 2018). Moreover, in metabolic deprivation states, as observed in ischemic conditions and MS, oligodendrocytes increase glycolytic metabolism for their own survival and lose myelinating functions.…”

Section: Metabolic Regulation Of Glial Phenotypic Changesmentioning

confidence: 99%

Metabolic Regulation of Glial Phenotypes: Implications in Neuron–Glia Interactions and Neurological Disorders

Afridi

Kim

Rahman

et al. 2020

Front. Cell. Neurosci.

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Glial cells are multifunctional, non-neuronal components of the central nervous system with diverse phenotypes that have gained much attention for their close involvement in neuroinflammation and neurodegenerative diseases. Glial phenotypes are primarily characterized by their structural and functional changes in response to various stimuli, which can be either neuroprotective or neurotoxic. The reliance of neurons on glial cells is essential to fulfill the energy demands of the brain for its proper functioning. Moreover, the glial cells perform distinct functions to regulate their own metabolic activities, as well as work in close conjunction with neurons through various secreted signaling or guidance molecules, thereby constituting a complex network of neuron-glial interactions in health and disease. The emerging evidence suggests that, in disease conditions, the metabolic alterations in the glial cells can induce structural and functional changes together with neuronal dysfunction indicating the importance of neuron-glia interactions in the pathophysiology of neurological disorders. This review covers the recent developments that implicate the regulation of glial phenotypic changes and its consequences on neuron-glia interactions in neurological disorders. Finally, we discuss the possibilities and challenges of targeting glial metabolism as a strategy to treat neurological disorders.

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Monocarboxylate transporter 1 and the vulnerability of oligodendrocyte lineage cells to metabolic stresses

Abstract: Taken together, this study shows that MCT1 plays a role in the responses of OPCs and OLs to metabolic and ischemic stresses and suggests that redistribution of energy substrates is a determinant in white matter injury.

Cited by 26 publications

References 18 publications

Pyruvate enhances M1 microglial polarization via NF-κB/MCT1/iNOS signaling axis under low glucose condition

Pyruvate enhances M1 microglial polarization via NF-κB/MCT1/iNOS signaling axis under low glucose condition

Oligodendrocyte Bioenergetics in Health and Disease

Metabolic Regulation of Glial Phenotypes: Implications in Neuron–Glia Interactions and Neurological Disorders

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