Is there a role for pyruvate dehydrogenase-phosphatase in the re-activation of hepatic pyruvate dehydrogenase complex after re-feeding?

The enzymic activity of the mammalian pyruvate dehydrogenase complex is regulated by the phosphorylation of three serine residues (sites 1, 2 and 3) located on the E1 component of the complex. Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (PDK1, PDK2, PDK3 and PDK4) differ in their abilities to phosphorylate the enzyme. PDK1 can phosphorylate all three sites, whereas PDK2, PDK3 and PDK4 each phosphorylate only site 1 and site 2. Although PDK2 phosphorylates site 1 and 2, it incorporates less phosphate in site 2 than PDK3 or PDK4. As a result, the amount of phosphate incorporated by each isoenzyme decreases in the order PDK1>PDK3PDK4>PDK2. Significantly, binding of the coenzyme thiamin pyrophosphate to pyruvate dehydrogenase alters the rates and stoichiometries of phosphorylation of the individual sites. First, the rate of phosphorylation of site 1 by all isoenzymes of kinase is decreased. Secondly, thiamin pyrophosphate markedly decreases the amount of phosphate that PDK1 incorporates in sites 2 and 3 and that PDK2 incorporates in site 2. In contrast, the coenzyme does not significantly affect the total amount of phosphate incorporated in site 2 by PDK3 and PDK4, but instead decreases the rate of phosphorylation of this site. Furthermore, pyruvate dehydrogenase complex phosphorylated by the individual isoenzymes of kinase is reactivated at different rates by pyruvate dehydrogenase phosphatase. Both isoenzymes of phosphatase (PDP1 and PDP2) readily reactivate the complex phosphorylated by PDK2. When pyruvate dehydrogenase is phosphorylated by other isoenzymes, the rates of reactivation decrease in the order PDK4PDK3> PDK1. Taken together, results reported here strongly suggest that the major determinants of the activity state of pyruvate dehydrogenase in mammalian tissues include the phosphorylation site specificity of isoenzymes of kinase in addition to the absolute amounts of kinase and phosphatase protein expressed in mitochondria.

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Regulation of the Human Pyruvate Dehydrogenase Complex

Clinical Science ◽

10.1042/cs0510445 ◽

1976 ◽

Vol 51 (5) ◽

pp. 445-452 ◽

Cited By ~ 2

Author(s):

D. Stansbie

Keyword(s):

Pyruvate Dehydrogenase ◽

Human Heart ◽

Pyruvate Dehydrogenase Complex ◽

Human Adipose Tissue ◽

Terminal Phosphate Group ◽

Mammalian Tissues ◽

High Level ◽

Pyruvate Dehydrogenase Phosphatase ◽

Thiamin Pyrophosphate ◽

Dehydrogenase Complex

1. The pyruvate dehydrogenase complex from human heart has been partially purified and shown to be regulated by a phosphorylation-dephosphorylation cycle similar to that previously found for other mammalian tissues. 2. Incubation of the complex with ATP (2 mmol/l) led to its inactivation associated with the concomitant incorporation into the protein of 32P from the terminal phosphate group of the ATP. Pyruvate, ADP, thiamin pyrophosphate and dichloroacetate diminished the rate of inactivation by ATP. 3. Pyruvate dehydrogenase phosphatase from human heart requires Mg2+ for activity and is sensitive to Ca2+ at concentrations of a few μmol/l. Similar ionic requirements of the skeletal muscle phosphatase have been demonstrated in a crude tissue extract. 4. The activity of pyruvate dehydrogenase in human adipose tissue was less than 10% of typical values in rats. This could be due to the high level of dietary fat consumed by humans, which is known to repress the enzyme activity in rats.

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A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency

JIMD Reports ◽

10.1002/jmd2.12054 ◽

2019 ◽

Vol 48 (1) ◽

pp. 26-35 ◽

Cited By ~ 2

Author(s):

Jirair K. Bedoyan ◽

Leah Hecht ◽

Shulin Zhang ◽

Stacey Tarrant ◽

Ann Bergin ◽

...

Keyword(s):

Pyruvate Dehydrogenase ◽

Pyruvate Dehydrogenase Complex ◽

Catalytic Subunit ◽

Null Mutation ◽

Subunit Gene ◽

Complex Deficiency ◽

Pyruvate Dehydrogenase Phosphatase ◽

Pyruvate Dehydrogenase Complex Deficiency ◽

Dehydrogenase Complex

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Abnormal Lipid Droplets Accumulation Induced Cognitive Deficits in Obstructive Sleep Apnea Syndrome Mice via JNK/SREBP/ACC Pathway but Not Through PDP1/PDC Pathway

10.21203/rs.3.rs-648813/v2 ◽

2021 ◽

Author(s):

Dongze Li ◽

Yan Yu ◽

Na Xu ◽

Wanting Li ◽

Yanyan Hou ◽

...

Keyword(s):

Cognitive Deficits ◽

Pyruvate Dehydrogenase ◽

Intermittent Hypoxia ◽

Lipid Droplets ◽

Salvia Miltiorrhiza ◽

Pyruvate Dehydrogenase Complex ◽

Acetyl Coa ◽

Obstructive Sleep ◽

Pyruvate Dehydrogenase Phosphatase ◽

Dehydrogenase Complex

Abstract The mechanisms of chronic intermittent hypoxia (CIH)-induced cognitive deficits remain unclear. Here, our study found that 12 weeks CIH treatment induced lipid droplets (LDs) accumulation in hippocampal neurocytes of C57BL/6 mice, and caused severe neuro damage including neuron lesions, neuroblast (NB) apoptosis and abnormal glial activation. Studies have shown that the neuronal metabolism disorders might contribute to the CIH induced-hippocampal impairment. Mechanistically, the results showed that pyruvate dehydrogenase complex E1ɑ subunit (PDHA1) and the pyruvate dehydrogenase complex (PDC) activator pyruvate dehydrogenase phosphatase 1 (PDP1) did not noticeable change after intermittent hypoxia. Consistent with those results, the level of Acetyl-CoA in hippocampus did not significantly change after CIH exposure. Interestingly, we found that CIH produced large quantities of ROS, which activated the JNK/SREBP/ACC pathway in neurocytes. ACC catalyzed the carboxylation of Acetyl-CoA to malonyl-CoA and then more lipid acids were synthesized, which finally caused aberrant LDs accumulation. Therefore, the JNK/SREBP/ACC pathway played a crucial role in the cognitive deficits caused by LDs accumulation after CIH exposure. Additionally, LDs were peroxidized by the high level of ROS under CIH conditions. Together, lipid metabolic disorders contributed to neurocytes damage, which ultimately caused behavioral dysfunction. An active component of Salvia miltiorrhiza, SMND-309, dramatically alleviated these injuries and improved cognitive deficits of CIH mice.

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Abnormal Lipid Droplets Accumulation Induced Cognitive Deficits in Obstructive Sleep Apnea Syndrome Mice via JNK/SREBP/ACC Pathway but Not Through PDP1/PDC Pathway

10.21203/rs.3.rs-648813/v1 ◽

2021 ◽

Author(s):

Dongze Li ◽

Yan Yu ◽

Na Xu ◽

Wanting Li ◽

Yanyan Hou ◽

...

Keyword(s):

Cognitive Deficits ◽

Pyruvate Dehydrogenase ◽

Intermittent Hypoxia ◽

Lipid Droplets ◽

Active Component ◽

Salvia Miltiorrhiza ◽

Pyruvate Dehydrogenase Complex ◽

Acetyl Coa ◽

Pyruvate Dehydrogenase Phosphatase ◽

Dehydrogenase Complex

Abstract IntroductionThe mechanisms of chronic intermittent hypoxia (CIH)-induced cognitive deficits remain unclear. Studies have shown that the neuronal metabolism disorders might contribute to the CIH induced-hippocampal impairment. MethodsWe assessed the CIH exposure influences of C57BL/6 mice on the activity of nerve, measured projects related to lipid metabolism, and treated with drugs SMND-309. ResultsOur study found that 12 weeks CIH treatment induced lipid droplets (LDs) accumulation in hippocampal neurocytes of mice, and caused severe neuro damage including neuron lesions, neuroblast (NB) apoptosis and abnormal glial activation. Mechanistically, the results showed that pyruvate dehydrogenase complex E1ɑ subunit (PDHA1) and the pyruvate dehydrogenase complex (PDC) activator pyruvate dehydrogenase phosphatase 1 (PDP1) did not noticeable change after intermittent hypoxia. Consistent with those results, the level of Acetyl-CoA in hippocampus did not significantly change after CIH exposure. Interestingly, we found that CIH produced large quantities of ROS, which activated the JNK/SREBP/ACC pathway in neurocytes. ACC catalyzed the carboxylation of Acetyl-CoA to malonyl-CoA and then more lipid acids were synthesized, which finally caused aberrant LDs accumulation. Additionally, LDs were peroxidized by the high level of ROS under CIH conditions. An active component of Salvia miltiorrhiza, SMND-309, dramatically alleviated these injuries and improved cognitive deficits of CIH mice. ConclusionTherefore, the JNK/SREBP/ACC pathway played a crucial role in the cognitive deficits caused by LDs accumulation after CIH exposure. Together, lipid metabolic disorders contributed to neurocytes damage, which ultimately caused behavioral dysfunction. An active component of Salvia miltiorrhiza, SMND-309, dramatically alleviated these injuries and improved cognitive deficits of CIH mice.

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Abnormal lipid droplets accumulation induced cognitive deficits in obstructive sleep apnea syndrome mice via JNK/SREBP/ACC pathway but not through PDP1/PDC pathway

Molecular Medicine ◽

10.1186/s10020-021-00427-8 ◽

2022 ◽

Vol 28 (1) ◽

Author(s):

Dongze Li ◽

Na Xu ◽

Yanyan Hou ◽

Wenjing Ren ◽

Na Zhang ◽

...

Keyword(s):

Cognitive Deficits ◽

Pyruvate Dehydrogenase ◽

Intermittent Hypoxia ◽

Lipid Droplets ◽

Pyruvate Dehydrogenase Complex ◽

Acetyl Coa ◽

Glia Cells ◽

Obstructive Sleep ◽

Pyruvate Dehydrogenase Phosphatase ◽

Dehydrogenase Complex

AbstractThe mechanisms of chronic intermittent hypoxia (CIH)-induced cognitive deficits remain unclear. Here, our study found that about 3 months CIH treatment induced lipid droplets (LDs) accumulation in hippocampal nerve and glia cells of C57BL/6 mice, and caused severe neuro damage including neuron lesions, neuroblast (NB) apoptosis and abnormal glial activation. Studies have shown that the neuronal metabolism disorders might contribute to the CIH induced-hippocampal impairment. Mechanistically, the results showed that pyruvate dehydrogenase complex E1ɑ subunit (PDHA1) and the pyruvate dehydrogenase complex (PDC) activator pyruvate dehydrogenase phosphatase 1 (PDP1) did not noticeable change after intermittent hypoxia. Consistent with those results, the level of Acetyl-CoA in hippocampus did not significantly change after CIH exposure. Interestingly, we found that CIH produced large quantities of ROS, which activated the JNK/SREBP/ACC pathway in nerve and glia cells. ACC catalyzed the carboxylation of Acetyl-CoA to malonyl-CoA and then more lipid acids were synthesized, which finally caused aberrant LDs accumulation. Therefore, the JNK/SREBP/ACC pathway played a crucial role in the cognitive deficits caused by LDs accumulation after CIH exposure. Additionally, LDs were peroxidized by the high level of ROS under CIH conditions. Together, lipid metabolic disorders contributed to nerve and glia cells damage, which ultimately caused behavioral dysfunction. An active component of Salvia miltiorrhiza, SMND-309, dramatically alleviated these injuries and improved cognitive deficits of CIH mice.

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