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Acylation of the Rat Brain Proteins is Affected by the Inhibition of Pyruvate Dehydrogenase in vivo

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Abstract

Organism adaptation to metabolic challenges requires coupling of metabolism to gene expression. In this regard, acylations of histones and metabolic proteins acquire significant interest. We hypothesize that adaptive response to inhibition of a key metabolic process, catalyzed by the acetyl-CoA-generating pyruvate dehydrogenase (PDH) complex, is mediated by changes in the protein acylations. The hypothesis is tested by intranasal administration to animals of PDH-specific inhibitors acetyl(methyl)phosphinate (AcMeP) or acetylphosphonate methyl ester (AcPMe), followed by the assessment of physiological parameters, brain protein acylation, and expression/phosphorylation of PDHA subunit. At the same dose, AcMeP, but not AcPMe, decreases acetylation and increases succinylation of the brain proteins with apparent molecular masses of 15-20 kDa. Regarding the proteins of 30-50 kDa, a strong inhibitor AcMeP affects acetylation only, while a less efficient AcPMe mostly increases succinylation. The unchanged succinylation of the 30-50 kDa proteins after the administration of AcMeP coincides with the upregulation of desuccinylase SIRT5. No significant differences between the levels of brain PDHA expression, PDHA phosphorylation, parameters of behavior or ECG are observed in the studied animal groups. The data indicate that the short-term inhibition of brain PDH affects acetylation and/or succinylation of the brain proteins, that depends on the inhibitor potency, protein molecular mass, and acylation type. The homeostatic nature of these changes is implied by the stability of physiological parameters after the PDH inhibition.

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Abbreviations

MDH:

malate dehydrogenase

OGDH:

2-oxoglutarate dehydrogenase (alpha-ketoglutarate dehydrogenase)

PDH:

pyruvate dehydrogenase

PDHA:

alpha subunit of PDH

RMSSD:

the root mean square of successive differences in R-R intervals

R-R interval:

the interval between the heartbeats

SD:

the standard deviation of R-R interval

SI:

stress index

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Funding

This work was supported by the Russian Science Foundation (grant no. 18-14-00116 to V.I.B.).

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Authors and Affiliations

  1. Belozersky Institute of Physico-Chemical Biology, Department of Biokinetics, Lomonosov Moscow State University, 119234, Moscow, Russia

    Vasily A. Aleshin, Alexey V. Kazantsev, Anastasia V. Graf & Victoria I. Bunik

  2. Department of Biochemistry, Sechenov University, 119048, Moscow, Russia

    Vasily A. Aleshin & Victoria I. Bunik

  3. Faculty of Biology, Lomonosov Moscow State University, 119234, Moscow, Russia

    Daria A. Sibiryakina & Anastasia V. Graf

  4. Faculty of Chemistry, Lomonosov Moscow State University, 119234, Moscow, Russia

    Alexey V. Kazantsev

  5. Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234, Moscow, Russia

    Victoria I. Bunik

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  1. Vasily A. Aleshin
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Contributions

V.I.B developed the concept, supervised the study, wrote and edited the manuscript, obtained the funding, and administered the project. A.V.G. designed, supervised, and analyzed animal experiments; V.A.A. studied protein acylations, validated and visualized biochemical results; D.A.S. performed animal experiments and studied expression and phosphorylation of PDHA; A.V.K. provided the pyruvate analogs. All the co-authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Victoria I. Bunik.

Ethics declarations

All animal experiments were performed according to the guidelines of the Declaration of Helsinki and were approved by Bioethics Committee of Lomonosov Moscow State University (protocol no. 139-a from 11 November 2021). The authors declare no conflict of interest. The funding sponsors had no role in the design of the study, collection, analysis, and interpretation of the data, writing of the manuscript, and decision to publish the results.

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Aleshin, V.A., Sibiryakina, D.A., Kazantsev, A.V. et al. Acylation of the Rat Brain Proteins is Affected by the Inhibition of Pyruvate Dehydrogenase in vivo. Biochemistry Moscow 88, 105–118 (2023). https://doi.org/10.1134/S0006297923010091

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