Overexpression of Pyruvate Dehydrogenase Kinase 1 and Lactate Dehydrogenase A in Nerve Cells Confers Resistance to Amyloid β and Other Toxins by Decreasing Mitochondrial Respiration and Reactive Oxygen Species Production

Newington, Jordan T.; Rappon, Tim; Albers, Shawn; Wong, Daisy Y.L.; Rylett, R. Jane; Cumming, Robert

doi:10.1074/jbc.m112.366195

Cited by 97 publications

(94 citation statements)

References 57 publications

(132 reference statements)

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“…PDK1 phosphorylates components of the PDH complex in the mitochondria (22, 23). This inhibitory phosphorylation suppresses pyruvate conversion to acetyl-CoA and thereby augmenting lactate production (22-24). We first confirmed that PDK1 knockdown reduces the phosphorylation of PDH-E1α (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

“…Pyruvate dehydrogenate kinase 1 (PDK1) is a key regulatory enzyme in glucose metabolism (22-24). PDK1 incites inhibitory phosphorylation on components of the pyruvate dehydrogenase (PDH) complex that converts pyruvate produced from glycolytic flux to acetyl-CoA (22-24).…”

Section: Introductionmentioning

confidence: 99%

“…PDK1 incites inhibitory phosphorylation on components of the pyruvate dehydrogenase (PDH) complex that converts pyruvate produced from glycolytic flux to acetyl-CoA (22-24). Pyruvate derived acetyl-CoA enters the TCA cycle that generates NADH that fuels the electron transport chain (ETC) for oxidative phosphorylation (25-27).…”

Section: Introductionmentioning

confidence: 99%

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Pyruvate Dehydrogenase Kinase 1 Participates in Macrophage Polarization via Regulating Glucose Metabolism

Tan

Xie

Cui

et al. 2015

The Journal of Immunology

266

228

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The M1 and M2 polarized phenotypes dictate distinctive roles for macrophages as they participate in inflammatory disorders. There has been growing interest in the role of cellular metabolism in macrophage polarization. However, it is currently unclear if different aspects of a specific metabolic program coordinately regulate this cellular process. In this study, we found that pyruvate dehydrogenate kinase 1 (PDK1), a key regulatory enzyme in glucose metabolism, plays an important role in the differential activation of macrophages. Knockdown of PDK1 diminished M1, whereas it enhanced M2 activation of macrophages. Mechanistically, PDK1 knockdown led to diminished aerobic glycolysis in M1 macrophages, which likely accounts for the attenuated inflammatory response in these cells. Furthermore, we found that mitochondrial respiration is enhanced during and required by the early activation of M2 macrophages. Suppression of glucose oxidation, but not that of fatty acids, inhibits this process. Consistent with its inhibitory role in early M2 activation, knockdown of PDK1 enhanced mitochondrial respiration in macrophages. Our data suggest that two arms of the glucose metabolism synergistically regulate the differential activation of macrophages. Our findings also highlight the central role of PDK1 in this event via controlling glycolysis and glucose oxidation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pyruvate Dehydrogenase Kinase 1 Participates in Macrophage Polarization via Regulating Glucose Metabolism

Tan

Xie

Cui

et al. 2015

The Journal of Immunology

266

228

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“…This treatment promoted aerobic glycolysis and protected against glutamate-mediated oxidative damage. Finally, overexpression of Pdk1 or lactate dehydrogenase A in the B12 neuronal cell line was shown to cause a decrease of mitochondrial respiration and to provide protection against amyloid ␤ toxicity (35,36). Together, these and other studies have shown that genetic or pharmacological manipulation of energy metabolism can protect cells against oxidative damage and cell death.…”

Section: Discussionmentioning

confidence: 96%

Synaptic Activity Drives a Genomic Program That Promotes a Neuronal Warburg Effect

Bas‐Orth

Tan²,

Lau

et al. 2017

Journal of Biological Chemistry

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Edited by F. Anne StephensonSynaptic activity drives changes in gene expression to promote long lasting adaptations of neuronal structure and function. One example of such an adaptive response is the buildup of acquired neuroprotection, a synaptic activity-and gene transcription-mediated increase in the resistance of neurons against harmful conditions. A hallmark of acquired neuroprotection is the stabilization of mitochondrial structure and function. We therefore re-examined previously identified sets of synaptic activity-regulated genes to identify genes that are directly linked to mitochondrial function. In mouse and rat primary hippocampal cultures, synaptic activity caused an up-regulation of glycolytic genes and a concomitant down-regulation of genes required for oxidative phosphorylation, mitochondrial biogenesis, and maintenance. Changes in metabolic gene expression were induced by action potential bursting, but not by glutamate bath application activating extrasynaptic NMDA receptors. The specific and coordinate pattern of gene expression changes suggested that synaptic activity promotes a shift of neuronal energy metabolism from oxidative phosphorylation toward aerobic glycolysis, also known as the Warburg effect. The ability of neurons to up-regulate glycolysis has, however, been debated. We therefore used FACS sorting to show that, in mixed neuron glia co-cultures, activity-dependent regulation of metabolic gene expression occurred in neurons. Changes in gene expression were accompanied by changes in the phosphorylation-dependent regulation of the key metabolic enzyme, pyruvate dehydrogenase. Finally, increased synaptic activity caused an increase in the ratio of L-lactate production to oxygen consumption in primary hippocampal cultures. Based on these data we suggest the existence of a synaptic activity-mediated neuronal Warburg effect that may promote mitochondrial homeostasis and neuroprotection.Synaptic activity can drive changes in gene expression to promote long lasting adaptations of neuronal structure and function (1, 2). Examples of such gene transcription-dependent adaptive responses are the formation of long term memories, activity-dependent dendritic remodeling, and the buildup of acquired neuroprotection. The latter is defined as a synaptic activity-and gene transcription-mediated increase in the resistance of neurons against harmful conditions (3). We have previously identified a number of so-called activity-regulated inhibitor of death genes that are able to confer such neuroprotection (4, 5). Although the exact mechanisms through which those genes confer neuroprotection are not yet fully understood, the functional changes mediated by activity-regulated inhibitor of death genes all seem to result in the protection of mitochondria (5-7). In the present study, we re-examined the synaptic activity-regulated gene pool to search for additional genes that are more directly linked to mitochondrial function. We found activity-dependent changes in the expression of several genes that encode for...

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“…It has been reported in the cytoplasm, mitochondrion and nucleus [11][12][13]. The cytoplasmic isoform essentially mediates the conversion of pyruvate to lactate with the concomitant conversion of NADH to NAD + , a process pivotal during anaerobic respiration [14]. In the mitochondrion, LDH provides pyruvate, a moiety involved in a variety of functions, including the production of energy [11].…”

Section: Introductionmentioning

confidence: 99%

Nuclear lactate dehydrogenase modulates histone modification in human hepatocytes

Castonguay

Auger

Thomas

et al. 2014

Biochemical and Biophysical Research Communications

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Overexpression of Pyruvate Dehydrogenase Kinase 1 and Lactate Dehydrogenase A in Nerve Cells Confers Resistance to Amyloid β and Other Toxins by Decreasing Mitochondrial Respiration and Reactive Oxygen Species Production

Cited by 97 publications

References 57 publications

Pyruvate Dehydrogenase Kinase 1 Participates in Macrophage Polarization via Regulating Glucose Metabolism

Pyruvate Dehydrogenase Kinase 1 Participates in Macrophage Polarization via Regulating Glucose Metabolism

Synaptic Activity Drives a Genomic Program That Promotes a Neuronal Warburg Effect

Nuclear lactate dehydrogenase modulates histone modification in human hepatocytes

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