A mutation in the E2 subunit of the mitochondrial pyruvate dehydrogenase complex in Arabidopsis reduces plant organ size and enhances the accumulation of amino acids and intermediate products of 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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Amino acids critical for binding of autoantibody to an immunodominant conformational epitope of the pyruvate dehydrogenase complex subunit E2: Identification by phage display and site-directed mutagenesis

Molecular Immunology ◽

10.1016/j.molimm.2005.03.011 ◽

2006 ◽

Vol 43 (6) ◽

pp. 745-753 ◽

Cited By ~ 3

Author(s):

Marita Scealy ◽

Ian R. Mackay ◽

Merrill J. Rowley

Keyword(s):

Amino Acids ◽

Phage Display ◽

Pyruvate Dehydrogenase ◽

Pyruvate Dehydrogenase Complex ◽

Conformational Epitope ◽

Site Directed Mutagenesis ◽

Directed Mutagenesis ◽

Dehydrogenase Complex

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Inactivation of Pyruvate Dehydrogenase Kinase 2 by Mitochondrial Reactive Oxygen Species

Journal of Biological Chemistry ◽

10.1074/jbc.m112.400002 ◽

2012 ◽

Vol 287 (42) ◽

pp. 35153-35160 ◽

Cited By ~ 29

Author(s):

Thomas R. Hurd ◽

Yvonne Collins ◽

Irina Abakumova ◽

Edward T. Chouchani ◽

Bartlomiej Baranowski ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Pyruvate Dehydrogenase ◽

Pyruvate Dehydrogenase Complex ◽

Reactive Oxygen ◽

Tca Cycle ◽

Pyruvate Dehydrogenase Kinase ◽

Oxygen Species ◽

Complex Activity ◽

Cycle Enzyme ◽

Dehydrogenase Complex

Reactive oxygen species are byproducts of mitochondrial respiration and thus potential regulators of mitochondrial function. Pyruvate dehydrogenase kinase 2 (PDHK2) inhibits the pyruvate dehydrogenase complex, thereby regulating entry of carbohydrates into the tricarboxylic acid (TCA) cycle. Here we show that PDHK2 activity is inhibited by low levels of hydrogen peroxide (H2O2) generated by the respiratory chain. This occurs via reversible oxidation of cysteine residues 45 and 392 on PDHK2 and results in increased pyruvate dehydrogenase complex activity. H2O2 derives from superoxide (O2̇̄), and we show that conditions that inhibit PDHK2 also inactivate the TCA cycle enzyme, aconitase. These findings suggest that under conditions of high mitochondrial O2̇̄ production, such as may occur under nutrient excess and low ATP demand, the increase in O2̇̄ and H2O2 may provide feedback signals to modulate mitochondrial metabolism.

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The Pyruvate Dehydrogenase Complex in Sepsis: Metabolic Regulation and Targeted Therapy

Frontiers in Nutrition ◽

10.3389/fnut.2021.783164 ◽

2021 ◽

Vol 8 ◽

Author(s):

Zhenhua Zeng ◽

Qiaobing Huang ◽

Liangfeng Mao ◽

Jie Wu ◽

Sheng An ◽

...

Keyword(s):

Energy Metabolism ◽

Pyruvate Dehydrogenase ◽

Metabolic Regulation ◽

Pyruvate Dehydrogenase Complex ◽

Aerobic Oxidation ◽

Tca Cycle ◽

Protective Effects ◽

Multienzyme Complex ◽

Therapeutic Drugs ◽

Dehydrogenase Complex

Anaerobic glycolysis is the process by which glucose is broken down into pyruvate and lactate and is the primary metabolic pathway in sepsis. The pyruvate dehydrogenase complex (PDHC) is a multienzyme complex that serves as a critical hub in energy metabolism. Under aerobic conditions, pyruvate translocates to mitochondria, where it is oxidized into acetyl-CoA through the activation of PDHC, thereby accelerating aerobic oxidation. Both phosphorylation and acetylation affect PDHC activity and, consequently, the regulation of energy metabolism. The mechanisms underlying the protective effects of PDHC in sepsis involve the regulation on the balance of lactate, the release of inflammatory mediators, the remodeling of tricarboxylic acid (TCA) cycle, as well as on the improvement of lipid and energy metabolism. Therapeutic drugs that target PDHC activation for sepsis treatment include dichloroacetate, thiamine, amrinone, TNF-binding protein, and ciprofloxacin. In this review, we summarize the recent findings regarding the metabolic regulation of PDHC in sepsis and the therapies targeting PDHC for the treatment of this condition.

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BCKDK regulates the TCA cycle through PDC to ensure embryonic development in the absence of PDK family

10.1101/2020.03.22.002360 ◽

2020 ◽

Author(s):

Lia Heinemann-Yerushalmi ◽

Lital Bentovim ◽

Neta Felsenthal ◽

Ron Carmel Vinestock ◽

Nofar Michaeli ◽

...

Keyword(s):

Embryonic Development ◽

Pyruvate Dehydrogenase ◽

Pyruvate Dehydrogenase Complex ◽

Tca Cycle ◽

Bioinformatic Analysis ◽

Compensatory Mechanism ◽

The Tca Cycle ◽

Early Embryonic Lethality ◽

Branched Chain ◽

Ketoacid Dehydrogenase

AbstractPyruvate dehydrogenase kinases (PDK1-4) inhibit the TCA cycle by phosphorylating pyruvate dehydrogenase complex (PDC). Here, we show that the PDK family is dispensable for the survival of murine embryonic development and that BCKDK serves as a compensatory mechanism by inactivating PDC.First, we knocked out all fourPdkgenes one by one. Surprisingly,Pdktotal KO embryos developed and were born in expected ratios, but died by postnatal day 4 due to hypoglycemia or ketoacidosis.Finding that PDC was phosphorylated in these embryos suggested that another kinase compensates for the PDK family. Bioinformatic analysis implicated brunch chain ketoacid dehydrogenase kinase (Bckdk), a key regulator of branched chain amino acids (BCAA) catabolism. Indeed, knockout ofBckdkand thePdkfamily led to loss of PDC phosphorylation, increment in PDC activity, elevation of Pyruvate flux into the TCA and early embryonic lethality. These findings reveal a new regulatory crosstalk hardwiring BCAA and glucose catabolic pathways, which feed the TCA cycle.

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