Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Phosphonate Inhibitors of Pyruvate Dehydrogenase Perturb Homeostasis of Amino Acids and Protein Succinylation in the Brain

Artem V. Artiukhov
,
Vasily A. Aleshin
ORCID logo ,
Irina S. Karlina
,
Alexey V. Kazantsev
* ,
Daria A. Sibiryakina
,
Alexander L. Ksenofontov
,
Nikolay V. Lukashev
,
Anastasia V. Graf
ORCID logo ,
Victoria I. Bunik
ORCID logo
Version 1 : Received: 1 October 2022 / Approved: 3 October 2022 / Online: 3 October 2022 (12:11:50 CEST)

A peer-reviewed article of this Preprint also exists.

Artiukhov, A.V.; Aleshin, V.A.; Karlina, I.S.; Kazantsev, A.V.; Sibiryakina, D.A.; Ksenofontov, A.L.; Lukashev, N.V.; Graf, A.V.; Bunik, V.I. Phosphonate Inhibitors of Pyruvate Dehydrogenase Perturb Homeostasis of Amino Acids and Protein Succinylation in the Brain. Int. J. Mol. Sci. 2022, 23, 13186. Artiukhov, A.V.; Aleshin, V.A.; Karlina, I.S.; Kazantsev, A.V.; Sibiryakina, D.A.; Ksenofontov, A.L.; Lukashev, N.V.; Graf, A.V.; Bunik, V.I. Phosphonate Inhibitors of Pyruvate Dehydrogenase Perturb Homeostasis of Amino Acids and Protein Succinylation in the Brain. Int. J. Mol. Sci. 2022, 23, 13186.

Abstract

Mitochondrial pyruvate dehydrogenase complex (PDHC) is essential for the brain glucose and neurotransmitter metabolism, dysregulated in many pathologies. Using specific inhibitors of PDHC in vivo, we determine biochemical and physiological responses to PDHC dysfunction. Dose dependence of the responses to membrane-permeable dimethyl acetylphosphonate (Ac-PMe2) is non-monotonous. Primary decreases in glutathione and its redox potential, methionine and ethanolamine are alleviated with increasing PDHC inhibition, the alleviation accompanied by physiological changes. Comparison of 39 brain biochemical parameters after administration of four phosphinate and phosphonate analogs of pyruvate at a fixed dose of 0.1 mmol/kg reveals no primary, but the secondary changes, such as activation of 2-oxoglutarate dehydrogenase complex (OGDHC) and decreased levels of glutamate, isoleucine and leucine. The accompanying decreases in RMSSD of ECG and freezing time are most pronounced after administration of me-thyl acetylphosphinate and dimethyl acetylphosphonate. The levels of PDHA1 expression and phosphorylation, sirtuin 3 and total protein acetylation are not significantly changed by the PDHC inhibitors that affect the brain protein succinylation and glutarylation. Thus, decreased production of the tricarboxylic acid cycle substrate acetyl-CoA by inhibited PDHC is compen-sated by increased degradation of amino acids through the cycle with activated OGDHC, increas-ing total protein succinylation and decreasing anxiety indicators.

Keywords

branched chain 2-oxo acids; 2-oxoglutarate dehydrogenase; pyruvate dehydrogenase; phospho-nate and phosphinate analogs of pyruvate; protein succinylation; protein acetylation; protein glutarylation; sirtuin 3; sirtuin 5; anxiety

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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