Metabolic reorganization in winter: Regulation of pyruvate dehydrogenase (PDH) during long-term freezing and anoxia

Al-attar, Rasha; Wijenayake, Sanoji; Storey, Kenneth B.

doi:10.1016/j.cryobiol.2019.01.006

Cited by 19 publications

(11 citation statements)

References 51 publications

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“…Four PDHK isozymes occur in vertebrates and catalyze the inhibitory phosphorylation of PDH at three serine residues (S232, S293, S300) of the catalytic E1α subunit. In response to freezing, wood frog liver showed a 3.0‐fold increase in PDHK1 protein expression and a 1.7‐fold increase in PDHK3, compared with controls and this was consistent with a 2.3‐fold increase in overall S300 phosphorylation in liver of frozen frogs . Both PDHK protein levels and p‐PDH(S300) content were reversed after an 8 hr thaw.…”

Section: Mitochondrial Metabolic Enzymes and Adaptation To Freezingsupporting

confidence: 64%

“…In response to freezing, wood frog liver showed a 3.0-fold increase in PDHK1 protein expression and a 1.7-fold increase in PDHK3, compared with controls and this was consistent with a 2.3-fold increase in overall S300 phosphorylation in liver of frozen frogs. 19 Both PDHK protein levels and p-PDH(S300) content were reversed after an 8 hr thaw. By contrast, PDHKs did not change significantly in liver in response to a 24-hr anoxia exposure or in skeletal muscle in response to freezing.…”

Section: Pyruvate Dehydrogenasementioning

confidence: 95%

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Mitochondria, metabolic control and microRNA: Advances in understanding amphibian freeze tolerance

Storey

2019

BioFactors

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Winter survival for many animal species depends freeze tolerance, a capacity to endure the conversion of as much as 65–70% of total body water into extracellular ice while reorganizing metabolism to provide cells with cryoprotection against insults that include prolonged ischemia and hyperosmotic stress. Natural freeze tolerance involves not just de novo preservation mechanisms such as synthesis of high levels of cryoprotectants or novel proteins that manage ice formation, but also requires attention to and co‐ordination of many cellular processes. The present review examines recent studies of the freeze‐tolerant wood frog (Rana sylvatica) that probed previously unexplored areas of metabolic adaptation for freezing survival, with a particular emphasis on mitochondria. Post‐translational controls on enzyme function play a prominent role in resculpting metabolic responses of the wood frog to freezing including reversible phosphorylation control over fuel processing at the pyruvate dehydrogenase locus and modulation of antioxidant defense enzymes (Mn‐SOD, catalase). Enzymes involved in mitochondrial nitrogen metabolism (glutamate dehydrogenase, carbamoyl phosphate synthetase) are also differentially regulated during freezing but by different post‐translational modifications including ADP‐ribosylation, lysine acetylation or glutarylation. The action of microRNAs in mediating post‐translational controls on gene expression aid the suppression of energy‐expensive (cell cycle) or destructive (apoptosis) processes in the frozen state while also providing storage of transcripts that will be immediately available for repair or reactivation of metabolic processes after thawing. The effects of low temperature in strengthening mRNA–microRNA interactions can also provide a passive mechanism of metabolic suppression in the frozen state.

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Section: Mitochondrial Metabolic Enzymes and Adaptation To Freezingsupporting

confidence: 64%

Section: Pyruvate Dehydrogenasementioning

confidence: 95%

Mitochondria, metabolic control and microRNA: Advances in understanding amphibian freeze tolerance

Storey

2019

BioFactors

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“…Investigations by many laboratories over the past several decades emphasized the integral role of the mitochondrial pyruvate dehydrogenase complex (PDC) in regulating fuel metabolism and organismal homeostasis in health and during both physiologic and pathologic stress . Under aerobic conditions, PDC catalyzes the rate‐determining step in aerobic glucose oxidation by irreversibly decarboxylating glycolytically derived pyruvate to acetyl coenzyme A (acetyl‐CoA), which condenses with oxaloacetate to form citrate in the tricarboxylic acid (TCA) cycle.…”

Section: Introductionmentioning

confidence: 99%

Stimulating pyruvate dehydrogenase complex reduces itaconate levels and enhances TCA cycle anabolic bioenergetics in acutely inflamed monocytes

Zhu

Long

Zabalawi

et al. 2020

Journal of Leukocyte Biology

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The pyruvate dehydrogenase complex (PDC)/pyruvate dehydrogenase kinase (PDK) axis directs the universal survival principles of immune resistance and tolerance in monocytes by controlling anabolic and catabolic energetics. Immune resistance shifts to immune tolerance during inflammatory shock syndromes when inactivation of PDC by increased PDK activity disrupts the tricarboxylic acid (TCA) cycle support of anabolic pathways. The transition from immune resistance to tolerance also diverts the TCA cycle from citrate‐derived cis‐aconitate to itaconate, a recently discovered catabolic mediator that separates the TCA cycle at isocitrate and succinate dehydrogenase (SDH). Itaconate inhibits succinate dehydrogenase and its anabolic role in mitochondrial ATP generation. We previously reported that inhibiting PDK in septic mice with dichloroacetate (DCA) increased TCA cycle activity, reversed septic shock, restored innate and adaptive immune and organ function, and increased survival. Here, using unbiased metabolomics in a monocyte culture model of severe acute inflammation that simulates sepsis reprogramming, we show that DCA‐induced activation of PDC restored anabolic energetics in inflammatory monocytes while increasing TCA cycle intermediates, decreasing itaconate, and increasing amino acid anaplerotic catabolism of branched‐chain amino acids (BCAAs). Our study provides new mechanistic insight that the DCA‐stimulated PDC homeostat reconfigures the TCA cycle and promotes anabolic energetics in monocytes by reducing levels of the catabolic mediator itaconate. It further supports the theory that PDC is an energy sensing and signaling homeostat that restores metabolic and energy fitness during acute inflammation.

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“…These changes of DEGs indicated the increase of serine synthesis. The increased free serine level in the cytoplasm can allosterically activate pyruvate kinase (PYK) 32 and enhance the activity of pyruvate dehydrogenase (PDH) 33 . Therefore, we deduced that addition of urea in the medium increased PYK and PDH activity by elevating the plasma serine level.…”

Section: Resultsmentioning

confidence: 99%

The transcriptome analysis on urea response mechanism in the process of ergosterol synthesis by Cordyceps cicadae

Zhang

Liu

et al. 2021

Sci Rep

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Nitrogen source is required for the growth of Cordyceps cicadae and involved in the regulation of metabolite synthesis. In order to further investigate the regulatory effects of nitrogen sources on the ergosterol synthesis by C. cicadae. We first confirmed that urea could significantly increase the ergosterol synthesis. The transcriptome analysis showed that compared with biomass cultured in the control fermentation medium (CFM), 1340 differentially expressed genes (DEGs) were obtained by Gene Ontology (GO) annotation, and 312 DEGs were obtained by Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation from the biomass cultured in CFM + CO(NH2)2. Urea up-regulated D-3-phosphoglycerate dehydrogenase gene transcription level and down-regulated enolase and L-serine/L-threonine ammonialyase gene transcription level, increased serine synthesis, allosterically activate pyruvate kinase, to promote the synthesis of pyruvate and CH3CO ~ SCOA, the primer of ergosterol; Urea increase the genes transcription related with ergosterol synthesis by up-regulating the steroid regulatory element binding protein gene transcription levels. The transcriptome results were provided by those of qRT-PCR. Collectively, our finding provided valuable insights into the regulatory effect of nitrogen source on the ergosterol synthesis by C. cicadae.

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Metabolic reorganization in winter: Regulation of pyruvate dehydrogenase (PDH) during long-term freezing and anoxia

Cited by 19 publications

References 51 publications

Mitochondria, metabolic control and microRNA: Advances in understanding amphibian freeze tolerance

Mitochondria, metabolic control and microRNA: Advances in understanding amphibian freeze tolerance

Stimulating pyruvate dehydrogenase complex reduces itaconate levels and enhances TCA cycle anabolic bioenergetics in acutely inflamed monocytes

The transcriptome analysis on urea response mechanism in the process of ergosterol synthesis by Cordyceps cicadae

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