Pyruvate Dehydrogenase Kinases in the Nervous System: Their Principal Functions in Neuronal-glial Metabolic Interaction and Neuro-metabolic Disorders

Jha, Mithilesh Kumar; Jeon, Sangmin; Suk, Kyoungho

doi:10.2174/157015912804499528

Cited by 61 publications

(10 citation statements)

References 17 publications

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“…Cultured astrocytes expressed more PDK2 and PDK4 compared to neurons, consistent with the lower PDH activity and higher lactate production displayed by cultured astrocytes [64]. There is accumulating evidence that alterations in PDKs activity are linked to the development of several neurological disorders.…”

Section: Introductionmentioning

confidence: 65%

The pivotal role of pyruvate dehydrogenase kinases in metabolic flexibility

et al. 2014

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Metabolic flexibility is the capacity of a system to adjust fuel (primarily glucose and fatty acids) oxidation based on nutrient availability. The ability to alter substrate oxidation in response to nutritional state depends on the genetically influenced balance between oxidation and storage capacities. Competition between fatty acids and glucose for oxidation occurs at the level of the pyruvate dehydrogenase complex (PDC). The PDC is normally active in most tissues in the fed state, and suppressing PDC activity by pyruvate dehydrogenase (PDH) kinase (PDK) is crucial to maintain energy homeostasis under some extreme nutritional conditions in mammals. Conversely, inappropriate suppression of PDC activity might promote the development of metabolic diseases. This review summarizes PDKs’ pivotal role in control of metabolic flexibility under various nutrient conditions and in different tissues, with emphasis on the best characterized PDK4. Understanding the regulation of PDC and PDKs and their roles in energy homeostasis could be beneficial to alleviate metabolic inflexibility and to provide possible therapies for metabolic diseases, including type 2 diabetes (T2D).

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Section: Introductionmentioning

confidence: 65%

The pivotal role of pyruvate dehydrogenase kinases in metabolic flexibility

et al. 2014

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“…Pyruvate, an intermediate of glucose entering into the TCA cycle, was reduced in the glioma with IDH1 mutation, but the ratio of pyruvate to lactate did not differ between the glioma tissues with and without IDH1 mutation. To investigate how pyruvate enters into the TCA cycle, we measured protein expression level of PDK1 regulating the conversion of pyruvate to acetyl-CoA and pyruvate carboxylase (PCE) that carboxylates it to oxaloacetate . The levels of PDK1 was reduced and PCE increased in the glioma tissues with IDH1 mutation compared to IDH1 wild-type (Figure S3).…”

Section: Resultsmentioning

confidence: 99%

Integrated Metabolomics and Lipidomics Analyses Reveal Metabolic Reprogramming in Human Glioma with IDH1 Mutation

Zhou

Wang

et al. 2018

J. Proteome Res.

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Mutations in isocitrate dehydrogenase (IDH) 1 are high-frequency events in low-grade glioma and secondary glioblastoma, and IDH1 mutant gliomas are vulnerable to interventions. Metabolic reprogramming is a hallmark of cancer. In this study, comprehensive metabolism investigation of clinical IDH1 mutant glioma specimens was performed to explore its specific metabolic reprogramming in real microenvironment. Massive metabolic alterations from glycolysis to lipid metabolism were identified in the IDH1 mutant glioma tissue when compared to IDH1 wild-type glioma. Of note, tricarboxylic acid (TCA) cycle intermediates were in similar levels in both groups, with more pyruvate found entering the TCA cycle in IDH1 mutant glioma. The pool of fatty acyl chains was also reduced, displayed as decreased triglycerides and sphingolipids, although membrane phosphatidyl lipids were not changed. The lower fatty acyl pool may be mediated by the lower protein expression levels of long-chain acyl-CoA synthetase 1 (ACSL1), ACSL4, and very long-chain acyl-CoA synthetase 3 (ACSVL3) in IDH1 mutant glioma. Lower ACSL1 was further found to contribute to the better survival of IDH1 mutant glioma patients based on the The Cancer Genome Atlas (TCGA) RNA sequencing data. Our research provides valuable insights into the tissue metabolism of human IDH1 mutant glioma and unravels new lipid-related targets.

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“…PDC exists in the mitochondrial matrix, is a rate-limiting enzyme in the TCA cycle, and can catalyze pyruvic acid oxidative decarboxylation into acetyl coenzyme A . PDC plays an important role in the energy metabolism of the mitochondrial respiratory chain and is closely linked to the aerobic oxidation of glucose, the TCA cycle and oxidative phosphorylation. − Therefore, MBC can increase the energy conservation of rice by promoting the pathways of glycolysis/gluconeogenesis and the TCA cycle.…”

Section: Resultsmentioning

confidence: 99%

Magnetic Biochar Mediates BDE-153 Accumulation and Metabolism in Rice (Oryza sativa L.) by Modulating Iron Plaque and the Fatty Acid Profile

Jia,

Ma,

White

et al. 2023

ACS EST Eng.

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The present study investigated the role of different doses of magnetic biochar (MBC, 0.65 to 6.7 g/L) in altering 2,2′,4,4′,5,5′hexabrominated diphenyl ether (BDE-153) accumulation and metabolism in rice by modulating iron plaque (IP) formation and the fatty acid (FA) profile as compared to biochar (BC). Both metabolomic and proteomic techniques were employed to further understand the molecular response in BDE-153-treated rice as affected by MBC co-exposure. Amendment with MBC enhanced IP formation by 3.0-and 2.5-fold as compared to BDE-153 and BC treatments, respectively. Treatment with MBC inhibited the FA content by up to 39.9% compared to BDE-153 alone, and a significant negative correlation between IP and total FA content (R 2 = 0.7851**) was found. Although there is no obvious dose dependency of MBC on BDE-153 accumulation in rice, the accumulation of BDE-153 in rice was inhibited by 31.4−81.9% upon exposure to different doses of MBC. The reductive debromination of BDE-153 on the root surface and inner roots was the greatest at 1.3 g/L MBC. The transfer of BDE-153 from the root surface to the inner root under MBC co-exposure was affected by root FAs and IP. MBC inhibited the expression of acyl carrier protein associated with FA synthesis, increased the expression of superoxide dismutase [Cu−Zn] and the content of FA 18:1 + 3O related to FAs metabolism, and consequently suppressed the FAs biosynthesis. In addition, IP formation under MBC treatments weakened the correlation between BDE-153 translocation and FA content. Taken together, these findings demonstrate the molecular mechanisms of BDE-153 accumulation and metabolism under MBC co-exposure and highlight the potential of this novel strategy for in situ remediation of BDE-153contaminated environments.

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Pyruvate Dehydrogenase Kinases in the Nervous System: Their Principal Functions in Neuronal-glial Metabolic Interaction and Neuro-metabolic Disorders

Cited by 61 publications

References 17 publications

The pivotal role of pyruvate dehydrogenase kinases in metabolic flexibility

The pivotal role of pyruvate dehydrogenase kinases in metabolic flexibility

Integrated Metabolomics and Lipidomics Analyses Reveal Metabolic Reprogramming in Human Glioma with IDH1 Mutation

Magnetic Biochar Mediates BDE-153 Accumulation and Metabolism in Rice (Oryza sativa L.) by Modulating Iron Plaque and the Fatty Acid Profile

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