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

被引:9
作者
Artiukhov, Artem V. [1 ,2 ]
Aleshin, Vasily A. [1 ,2 ]
Karlina, Irina S. [3 ]
Kazantsev, Alexey V. [1 ,4 ]
Sibiryakina, Daria A. [5 ]
Ksenofontov, Alexander L. [1 ]
Lukashev, Nikolay V.
Graf, Anastasia V. [1 ,5 ]
Bunik, Victoria I. [1 ,2 ,6 ]
机构
[1] Lomonosov Moscow State Univ, Dept Biokinet, AN Belozersky Inst Physicochem Biol, Moscow 119234, Russia
[2] Sechenov Univ, Dept Biochem, Moscow 105043, Russia
[3] Sechenov Univ, Dept Clin Med, Moscow 105043, Russia
[4] Lomonosov Moscow State Univ, Fac Chem, Moscow 119234, Russia
[5] Lomonosov Moscow State Univ, Fac Biol, Moscow 119234, Russia
[6] Lomonosov Moscow State Univ, Fac Bioengn & Bioinformat, Moscow 119234, Russia
基金
俄罗斯基础研究基金会;
关键词
branched chain 2-oxo acids; 2-oxoglutarate dehydrogenase; pyruvate dehydrogenase; phosphonate and phosphinate analogs of pyruvate; protein succinylation; protein acetylation; protein glutarylation; sirtuin; 3; 5; anxiety; ACETYL-COA; 2-OXOGLUTARATE DEHYDROGENASE; ACETYLCHOLINE METABOLISM; THIAMIN; VIABILITY; ANALOGS; MECHANISMS; DEFICITS; COMPLEX; ENZYMES;
D O I
10.3390/ijms232113186
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mitochondrial pyruvate dehydrogenase complex (PDHC) is essential for brain glucose and neurotransmitter metabolism, which is 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 (AcPMe2) 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. A 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 secondary changes, such as activation of 2-oxoglutarate dehydrogenase complex (OGDHC) and decreased levels of glutamate, isoleucine and leucine. The accompanying decreases in freezing time are most pronounced after administration of methyl acetylphosphinate and dimethyl acetylphosphonate. The PDHC inhibitors do not significantly change the levels of PDHA1 expression and phosphorylation, sirtuin 3 and total protein acetylation, but increase total protein succinylation and glutarylation, affecting sirtuin 5 expression. Thus, decreased production of the tricarboxylic acid cycle substrate acetyl-CoA by inhibited PDHC is compensated by increased degradation of amino acids through the activated OGDHC, increasing total protein succinylation/glutarylation. Simultaneously, parasympathetic activity and anxiety indicators decrease.
引用
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页数:17
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