Critical Role of Specific Ions for Ligand-Induced Changes Regulating Pyruvate Dehydrogenase Kinase Isoform 2†

ABSTRACT The prolyl-4-hydroxylase domain (PHD) enzymes are regarded as the molecular oxygen sensors. There is an interplay between oxygen availability and cellular metabolism, which in turn has significant effects on the functionality of innate immune cells, such as macrophages. However, if and how PHD enzymes affect macrophage metabolism are enigmatic. We hypothesized that macrophage metabolism and function can be controlled via manipulation of PHD2. We characterized the metabolic phenotypes of PHD2-deficient RAW cells and primary PHD2 knockout bone marrow-derived macrophages (BMDM). Both showed typical features of anaerobic glycolysis, which were paralleled by increased pyruvate dehydrogenase kinase 1 (PDK1) protein levels and a decreased pyruvate dehydrogenase enzyme activity. Metabolic alterations were associated with an impaired cellular functionality. Inhibition of PDK1 or knockout of hypoxia-inducible factor 1α (HIF-1α) reversed the metabolic phenotype and impaired the functionality of the PHD2-deficient RAW cells and BMDM. Taking these results together, we identified a critical role of PHD2 for a reversible glycolytic reprogramming in macrophages with a direct impact on their function. We suggest that PHD2 serves as an adjustable switch to control macrophage behavior.

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Critical Role of a Lipoyl Cofactor of the Dihydrolipoyl Acetyltransferase in the Binding and Enhanced Function of the Pyruvate Dehydrogenase Kinase

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.1993.1146 ◽

1993 ◽

Vol 190 (3) ◽

pp. 982-991 ◽

Cited By ~ 32

Author(s):

G.A. Radke ◽

K. Ono ◽

S. Ravindran ◽

T.E. Roche

Keyword(s):

Pyruvate Dehydrogenase ◽

Critical Role ◽

Pyruvate Dehydrogenase Kinase ◽

Dihydrolipoyl Acetyltransferase

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ANG II causes insulin resistance and induces cardiac metabolic switch and inefficiency: a critical role of PDK4

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00636.2012 ◽

2013 ◽

Vol 304 (8) ◽

pp. H1103-H1113 ◽

Cited By ~ 82

Author(s):

Jun Mori ◽

Osama Abo Alrob ◽

Cory S. Wagg ◽

Robert A. Harris ◽

Gary D. Lopaschuk ◽

...

Keyword(s):

Heart Failure ◽

Insulin Resistance ◽

Energy Metabolism ◽

Pyruvate Dehydrogenase ◽

Glucose Oxidation ◽

Critical Role ◽

Pyruvate Dehydrogenase Kinase ◽

Ang Ii ◽

Oxidation Rates

The renin-angiotensin system (RAS) may alter cardiac energy metabolism in heart failure. Angiotensin II (ANG II), the main effector of the RAS in heart failure, has emerged as an important regulator of cardiac hypertrophy and energy metabolism. We studied the metabolic perturbations and insulin response in an ANG II-induced hypertrophy model. Ex vivo heart perfusion showed that hearts from ANG II-treated mice had a lower response to insulin with significantly reduced rates of glucose oxidation in association with increased pyruvate dehydrogenase kinase 4 (PDK4) levels. Palmitate oxidation rates were significantly reduced in response to insulin in vehicle-treated hearts but remained unaltered in ANG II-treated hearts. Furthermore, phosphorylation of Akt was also less response to insulin in ANG II-treated wild-type (WT) mice, suggestive of insulin resistance. We evaluated the role of PDK4 in the ANG II-induced pathology and showed that deletion of PDK4 prevented ANG II-induced diastolic dysfunction and normalized glucose oxidation to basal levels. ANG II-induced reduction in the levels of the deacetylase, SIRT3, was associated with increased acetylation of pyruvate dehydrogenase (PDH) and a reduced PDH activity. In conclusion, our findings show that a combination of insulin resistance and decrease in PDH activity are involved in ANG II-induced reduction in glucose oxidation, resulting in cardiac inefficiency. ANG II reduces PDH activity via acetylation of PDH complex, as well as increased phosphorylation in response to increased PDK4 levels.

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Salinity‐induced changes in gene expression in the streptophyte alga Chara: The critical role of a rare Na + ‐ATPase

Journal of Phycology ◽

10.1111/jpy.13166 ◽

2021 ◽

Author(s):

Shaunna Phipps ◽

Charles F. Delwiche ◽

Mary A. Bisson

Keyword(s):

Gene Expression ◽

Critical Role ◽

Induced Changes

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The Role of Pyruvate Dehydrogenase Kinase in Diabetes and Obesity

Diabetes & Metabolism Journal ◽

10.4093/dmj.2014.38.3.181 ◽

2014 ◽

Vol 38 (3) ◽

pp. 181 ◽

Cited By ~ 42

Author(s):

In-Kyu Lee

Keyword(s):

Pyruvate Dehydrogenase ◽

Pyruvate Dehydrogenase Kinase ◽

Diabetes And Obesity

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Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Cancers ◽

10.3390/cancers12071731 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1731 ◽

Cited By ~ 1

Author(s):

Carina Neitzel ◽

Philipp Demuth ◽

Simon Wittmann ◽

Jörg Fahrer

Keyword(s):

Colorectal Cancer ◽

Energy Metabolism ◽

Pyruvate Dehydrogenase ◽

Pyruvate Dehydrogenase Complex ◽

Tca Cycle ◽

Dietary Factors ◽

Pyruvate Dehydrogenase Kinase ◽

Driver Mutations ◽

The Tca Cycle

Colorectal cancer (CRC) is among the most frequent cancer entities worldwide. Multiple factors are causally associated with CRC development, such as genetic and epigenetic alterations, inflammatory bowel disease, lifestyle and dietary factors. During malignant transformation, the cellular energy metabolism is reprogrammed in order to promote cancer cell growth and proliferation. In this review, we first describe the main alterations of the energy metabolism found in CRC, revealing the critical impact of oncogenic signaling and driver mutations in key metabolic enzymes. Then, the central role of mitochondria and the tricarboxylic acid (TCA) cycle in this process is highlighted, also considering the metabolic crosstalk between tumor and stromal cells in the tumor microenvironment. The identified cancer-specific metabolic transformations provided new therapeutic targets for the development of small molecule inhibitors. Promising agents are in clinical trials and are directed against enzymes of the TCA cycle, including isocitrate dehydrogenase, pyruvate dehydrogenase kinase, pyruvate dehydrogenase complex (PDC) and α-ketoglutarate dehydrogenase (KGDH). Finally, we focus on the α-lipoic acid derivative CPI-613, an inhibitor of both PDC and KGDH, and delineate its anti-tumor effects for targeted therapy.

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