Characterizing the regulation of pyruvate kinase in response to hibernation in ground squirrel liver (Urocitellus richardsonii)

Smolinski, Michael B.; Green, Stuart R.; Storey, Kenneth B.

doi:10.1016/j.cbpb.2020.110466

Cited by 5 publications

(3 citation statements)

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“…5 Examples of this biochemical opposition are the hyperarousal of acute stress and the torpor of hibernation and estivation. [6][7][8][9] A transition (trade-off) from energy consuming danger resistance to a hostile environment to a low energy state of disease tolerance also occurs during sepsis where pathogen resistance processes are balanced by mechanisms to limit collateral tissue damage. 4 Sepsis, however, fails the host's resistance-to-tolerance shift in 2 ways.…”

Section: The Mitochondrial Energy Demand and Supply Chain Separates D...mentioning

confidence: 99%

“…The progression from an organism's initial high energy consuming resistance to an invading pathogen to a low energy state of disease tolerance is a universal survival strategy preserved throughout evolution 5 . Examples of this biochemical opposition are the hyperarousal of acute stress and the torpor of hibernation and estivation 6–9 . A transition (trade‐off) from energy consuming danger resistance to a hostile environment to a low energy state of disease tolerance also occurs during sepsis where pathogen resistance processes are balanced by mechanisms to limit collateral tissue damage 4 .…”

Section: The Mitochondrial Energy Demand and Supply Chain Separates D...mentioning

confidence: 99%

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Sepsis, pyruvate, and mitochondria energy supply chain shortage

McCall

Zhu

Zabalawi

et al. 2022

Journal of Leukocyte Biology

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Balancing high energy-consuming danger resistance and low energy supply of disease tolerance is a universal survival principle that often fails during sepsis. Our research supports the concept that sepsis phosphorylates and deactivates mitochondrial pyruvate dehydrogenase complex control over the tricarboxylic cycle and the electron transport chain. StimulatIng mitochondrial energetics in septic mice and human sepsis cell models can be achieved by inhibiting pyruvate dehydrogenase kinases with the pyruvate structural analog dichloroacetate. Stimulating the pyruvate dehydrogenase complex by dichloroacetate reverses a disruption in the tricarboxylic cycle that induces itaconate, a key mediator of the disease tolerance pathway. Dichloroacetate treatment increases mitochondrial respiration and ATP synthesis, decreases oxidant stress, overcomes metabolic paralysis, regenerates tissue, organ, and innate and adaptive immune cells, and doubles the survival rate in a murine model of sepsis.

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Section: The Mitochondrial Energy Demand and Supply Chain Separates D...mentioning

confidence: 99%

Section: The Mitochondrial Energy Demand and Supply Chain Separates D...mentioning

confidence: 99%

Sepsis, pyruvate, and mitochondria energy supply chain shortage

McCall

Zhu

Zabalawi

et al. 2022

Journal of Leukocyte Biology

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“…4). Our group recently demonstrated elevated levels of both threonine and serine phosphorylation in the liver isoform of PK in response to hibernation in a ground squirrel species which also correlated with lower enzyme activity, though whether this represents a common mechanism of enzymatic control compared to the current study is uncertain (Smolinski et al ., 2020). From the observation in the present study, it seems likely that PK exists in at least two forms in the gall fly; a low‐phosphate form observed in the control larvae and a high‐phosphate form seen in the freeze‐exposed insects.…”

Section: Discussionmentioning

confidence: 99%

Regulation of an important glycolytic enzyme, pyruvate kinase, through phosphorylation in the larvae of a species of freeze‐tolerant insect, Eurosta solidaginis

Abboud

Green

Smolinski

et al. 2020

Insect Molecular Biology

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Larvae of the goldenrod gall fly, Eurosta solidaginis, rely on a freeze tolerance strategy to survive the sub‐zero temperatures of Canadian winter. Critical to their survival is the accumulation of polyol cryoprotectants and global metabolic rate depression, both of which require the regulation of glycolysis and reorganization of carbohydrate metabolism. This study explored the role that pyruvate kinase (PK) regulation plays in this metabolic reorganization. PK was purified from control (5 °C‐acclimated) and frozen (−15 °C‐acclimated) larvae and enzyme kinetic properties, structural stability, and post‐translational modifications were examined in both enzyme forms. The Km phosphoenolpyruvate (PEP) of frozen PK was 20% higher than that of control PK, whereas the Vmax of frozen PK was up to 50% lower than that of control PK at the lowest assay temperature, suggesting inhibition of the enzyme during the winter. Additionally, the activity and substrate affinity of both forms of PK decreased significantly at low assay temperatures, and both forms were regulated allosterically by a number of metabolites. Pro‐Q™ Diamond phosphoprotein staining and immunoblotting experiments demonstrated significantly higher threonine phosphorylation of PK from frozen animals while acetylation and methylation levels remained constant. Together, these results indicate that PK exists in two structurally distinct forms in E. solidaginis. In response to conditions mimicking the transition to winter, PK appears to be regulated to support metabolic rate depression, the accumulation of polyol cryoprotectants, and the need for extended periods of anaerobic carbohydrate metabolism to allow the animal to survive whole‐body freezing.

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