Tissue-specific kinase expression and activity regulate flux through the pyruvate dehydrogenase complex

Abstract

The pyruvate dehydrogenase complex (PDC) is a multienzyme assembly that converts pyruvate to acetyl-CoA. As pyruvate and acetyl-CoA play central roles in cellular metabolism, understanding PDC regulation is pivotal to understanding the larger metabolic network. The activity of mammalian PDC is regulated through reversible phosphorylation governed by at least four isozymes of pyruvate dehydrogenase kinase (PDK). Deciphering which kinase regulates PDC in organisms at specific times or places has been challenging. In this study, we analyzed mouse strains carrying targeted mutations of individual isozymes to explore their role in regulating PDC activity. Analysis of protein content of PDK isozymes in major metabolic tissues revealed that PDK1 and PDK2 were ubiquitously expressed, whereas PDK3 and PDK4 displayed a rather limited tissue distribution. Measurement of kinase activity showed that PDK1 is the principal isozyme regulating hepatic PDC. PDK2 was largely responsible for inactivation of PDC in tissues of muscle origin and brown adipose tissue (BAT). PDK3 was the principal kinase regulating pyruvate dehydrogenase activity in kidney and brain. In a well-fed state, the tissue levels of PDK4 protein were fairly low. In most tissues tested, PDK4 ablation had little effect on the overall rates of inactivation of PDC in kinase reaction. Taken together, these data strongly suggest that the activity of PDC is regulated by different isozymes in different tissues. Furthermore, it appears that the overall flux through PDC in a given tissue largely reflects the properties of the PDK isozyme that is principally responsible for the regulation of PDC activity in that tissue. This article contains Figs. S1-S6.

Vascular Calcification—New Insights into Its Mechanism

“…PDK, which consists of four isotypes, is a main regulator of the pyruvate dehydrogenase complex (PDC), a master regulator of cellular energy metabolism in mitochondria [195]. Among the four isotypes, the role of PDK4, in VC, by induction of osteogenic differentiation of VSMCs, was reported [196,197], while phosphorylation of PDHE1α was localized to calcified lesions in VC patients.…”

The Implications of PDK1–4 on Tumor Energy Metabolism, Aggressiveness and Therapy Resistance

“…One of the main enzymes regulating the metabolic shift in mammals is the mitochondrial PDC (20,21). It is composed of the pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3) and the E3 binding protein (E3BP) (4,22). The PDC catalyzes the irreversible conversion of pyruvate, nicotinamide adenine dinucleotide (NAD+) and coenzyme-A (CoA) into acetyl-CoA, NADH and CO 2 (4).…”

“…PDK1 is abundant in the cardiac muscle, pancreatic islets, and skeletal muscle and is expressed at lower levels in other tissues (20,22,23,(33)(34)(35). PDK2 on the contrary is ubiquitously expressed, with the highest expression levels in the heart, diaphragm, kidney, and red skeletal muscles (22). Other tissues such as liver, brain, testis, ovaries, and lung show lower PDK2 protein levels (22).…”

The “great” controlling nucleotide coenzymes

“…The increase in the Δ G′ of ATP observed in the working perfused heart led directly to the increase in physiological performance in animals and in endurance athletes . The same increase in acetyl coenzyme A (acetyl CoA) induced by the metabolism of d ‐β‐hydroxybutyrate in heart can also be potentially used as a therapy overcoming the impairment of brain PDH activity in Alzheimer's disease .…”