Inhibition of pyruvate dehydrogenase affects the brain protein acylation stronger than PDHA phosphorylation at Ser293

Abstract

Adaptation of an organism to metabolic challenges requires mechanisms coupling metabolism to gene expression. Acylations of metabolic and histone proteins acquire significant attention in this regard. We hypothesize that adaptive response to inhibition of a key metabolic process, catalyzed by the acetyl-CoA-generating pyruvate dehydrogenase (PDH) complex, may be mediated by changed protein acylations. The hypothesis is tested by intranasal administration to animals of PDH-specific inhibitors acetylmethylphosphinate (AcMeP) or methyl ester of acetylphosphonate (AcPMe), followed by assessment of physiological parameters, brain protein acylation system and expression/phosphorylation of PDHA subunit. At a fixed dose, AcMeP, but not AcPMe, decreases acetylation and increases succinylation of the brain proteins of apparent molecular mass of 15-20 kDa. Regarding the 30-50 kDa proteins, a strong inhibitor AcMeP affects acetylation only, while a less efficient AcPMe mostly increases succinylation. No increase in the succinylation of the 30-50 kDa proteins by AcMeP coincides with its induction of desuccinylase SIRT5, not observed in the AcPMe-treated animals. The brain PDHA expression or phosphorylation, the animal behavior or ECG do not significantly differ between the studied animal groups. The data indicate that a short-term inhibition of the brain PDH affects acetylation and/or succinylation of the brain proteins, dependent on the inhibitor potency, protein molecular mass and acylation type. Homeostatic nature of these changes is implied by stability of physiological parameters after the PDH inhibition.