Daytime Dependence of the Activity of the Rat Brain Pyruvate Dehydrogenase Corresponds to the Mitochondrial Sirtuin 3 Level and Acetylation of Brain Proteins, All Regulated by Thiamine Administration Decreasing Phosphorylation of PDHA Ser293

Abstract

Coupling glycolysis and mitochondrial tricarboxylic acid cycle, pyruvate dehydrogenase (PDH) complex (PDHC) is highly responsive to cellular demands through multiple mechanisms, including PDH phosphorylation. PDHC also produces acetyl-CoA for protein acetylation involved in circadian regulation of metabolism. Thiamine (vitamin B1) diphosphate (ThDP) is known to activate PDH as both coenzyme and inhibitor of the PDH inactivating kinases. Molecular mechanisms integrating the function of thiamine-dependent PDHC into general redox metabolism, underlie physiological fitness of a cell or an organism. Here, we characterize the daytime- and thiamine-dependent changes in the rat brain PDHC function, expression and phosphorylation, assessing their impact on protein acetylation and metabolic regulation. Morning administration of thiamine significantly downregulates both the PDH phosphorylation at Ser293 and SIRT3 protein level, the effects not observed upon the evening administration. This action of thiamine nullifies the daytime-dependent changes in the brain PDHC activity and mitochondrial acetylation, inducing diurnal difference in the cytosolic acetylation and acetylation of total brain proteins. Screening the daytime dependence of central metabolic enzymes and proteins of thiol/disulfide metabolism reveals that thiamine also cancels daily changes in the malate dehydrogenase activity, opposite to those of the PDHC activity. Correlation analysis indicates that thiamine abrogates the strong positive correlation between the total acetylation of the brain proteins and PDHC function. Simultaneously, thiamine heightens interplay between the expression of PDHC components and total acetylation or SIRT2 protein level. These thiamine effects on the brain acetylation system change metabolic impact of acetylation. The changes are exemplified by the thiamine enhancement of the SIRT2 correlations with metabolic enzymes and proteins of thiol-disulfide metabolism. Thus, we show the daytime- and thiamine-dependent changes in the function and phosphorylation of brain PDHC, contributing to regulation of the brain acetylation system and redox metabolism. The daytime-dependent action of thiamine on PDHC and SIRT3 may be of therapeutic significance in correcting perturbed diurnal regulation.

The pH-Dependent Controlled Release of Encapsulated Vitamin B1 from Liposomal Nanocarrier

“…To analyze the primer release data, the dissolution profiles were fitted by a non-linear technique using seven different kinetic models applying a self-developed and freely available routine [ 26 ], which was published previously by our research group. First- and second-order [ 27 , 28 ], Higuchi [ 29 ], Weibull [ 30 ], Korsmeyer–Peppas [ 31 ], Hopfenberg [ 32 ] and Hixon-Crowell [ 20 , 33 ] models were tested, where models take different physicochemical parameters into account. The goodness of fit is represented by the correlation coefficients (R 2 ), which can be seen in Figure 5 , in the case of the PBS ( Figure 5 a) and acidic ( Figure 5 b) medium, respectively.…”

“…In the presented work, vitamin B 1 was selected for the development of a liposomal-based colloidal drug carrier. Vitamin B 1 is one of the most important vitamins for the human body; its absence can lead to beriberi disease caused by impaired glucose oxidation and lack of pyruvate oxidation [ 20 ]. This essential compound also acts as a coenzyme of the enzyme that decarboxylates red tartaric acid.…”

P53 Protein Modulates Muscle Metabolism and Generates a Non-Genetic Risk Environment that Contributes to Triggering Amyotrophic Lateral Sclerosis

“…There are diurnal and thiamine-dependent changes in the function, expression, and phosphorylation of PDHC in the rat brain, and its impacts on protein acetylation and metabolic regulation have been evaluated. The morning administration of thiamine significantly regulated the phosphorylation of PDH at both the Ser293 and SIRT3 protein levels [56], but these effects were not observed with evening administration. This action of thiamine abrogates the diurnal dependent changes in brain PDHC activity and mitochondrial acetylation, inducing the diurnal differences in cytosolic acetylation and total brain protein acetylation.…”

“…3.5. Dysfunction in the pyruvate dehydrogenase enzyme and/or in its metabolic modulators (i.e., kinases and phosphatases) would prevent the passage of glycolysis into the Krebs cycle [55,56,57]. A family history of diabetes and/or epilepsy also suggests defects in this enzyme and is correlated with ALS disease (studies of confidential medical reports were obtained from clinical trials and references [58,59,60,61, 62]).…”

Delayed Impact of 2-Oxoadipate Dehydrogenase Inhibition on the Rat Brain Metabolism Is Linked to Protein Glutarylation

“…Finally, given the possible link between the OADH-dependent production of glutaryl residues and system of post-translational modification of proteins by glutarylation ( Figure 1 ), the levels of glutarylated proteins and deglutarylase sirtuin 5 in the brain are also included in the metabolic heatmap. Expression of the major mitochondrial deacetylase sirtuin 3 is determined in view of its involvement into the regulation of mitochondrial metabolism, particularly the enzymes of the amino acid metabolism ( 50 , 52 ).…”