Role of the Pyruvate Dehydrogenase Complex in Metabolic Remodeling: Differential Pyruvate Dehydrogenase Complex Functions in Metabolism

Abstract

Mitochondrial dysfunction is a hallmark of metabolic diseases such as obesity, type 2 diabetes mellitus, neurodegenerative diseases, and cancers. Dysfunction occurs in part because of altered regulation of the mitochondrial pyruvate dehydrogenase complex (PDC), which acts as a central metabolic node that mediates pyruvate oxidation after glycolysis and fuels the Krebs cycle to meet energy demands. Fine-tuning of PDC activity has been mainly attributed to post-translational modifications of its subunits, including the extensively studied phosphorylation and de-phosphorylation of the E1α subunit of pyruvate dehydrogenase (PDH), modulated by kinases (pyruvate dehydrogenase kinase [PDK] 1-4) and phosphatases (pyruvate dehydrogenase phosphatase [PDP] 1-2), respectively. In addition to phosphorylation, other covalent modifications, including acetylation and succinylation, and changes in metabolite levels via metabolic pathways linked to utilization of glucose, fatty acids, and amino acids, have been identified. In this review, we will summarize the roles of PDC in diverse tissues and how regulation of its activity is affected in various metabolic disorders.

Influenza and obesity: its odd relationship and the lessons for COVID-19 pandemic

“…Zhang et al proposed that leptin resistance was a cofactor for the 2009 A (H1N1) pandemic influenza, leptin being a major regulator of B cell maturation, development and function [13]. Similarly, obese patients may present with numerical and functional alterations of lymphocytes leading to impaired memory T cell responses and vaccine efficacy [14]. Obesity inhibits both virus-specific CD8 + T cell responses and antibody responses to the seasonal influenza vaccine; again a suboptimal macrophage functionality and maturation characteristic of the obese host may contribute to the poor vaccine response [15].…”

“…PDC is an important modulator of energy and metabolic homeostasis, and insulin resistance is associated with increased skeletal muscle pyruvate dehydrogenase kinase (PDK) that phosphorylates and inactivates PDC. Increased PDK4 expression in muscle has been observed in insulinresistant status, including obesity [14,30]. In mice infected by the H1N1 virus, there is a marked down-regulation of PDC activity and ATP level, with selective up-regulation of PDK4 in the skeletal muscles, heart, liver and lungs.…”

Beneficial Effects of Acetyl-DL-Leucine (ADLL) in a Mouse Model of Sandhoff Disease

“…We then tested ADLL's effect on glucose utilisation by examining enzymes that regulate aerobic glycolysis, via pyruvate dehydrogenase (PDH), and anaerobic glycolysis, via lactate dehydrogenase (LDH). PDH contains three subunits (E1, E2, E3), which convert the glycolysis product, pyruvate, to acetyl CoA, the prime substrate of the TCA cycle [35].…”

Stimulating pyruvate dehydrogenase complex reduces itaconate levels and enhances TCA cycle anabolic bioenergetics in acutely inflamed monocytes

“…Investigations by many laboratories over the past several decades emphasized the integral role of the mitochondrial pyruvate dehydrogenase complex (PDC) in regulating fuel metabolism and organismal homeostasis in health and during both physiologic and pathologic stress . Under aerobic conditions, PDC catalyzes the rate‐determining step in aerobic glucose oxidation by irreversibly decarboxylating glycolytically derived pyruvate to acetyl coenzyme A (acetyl‐CoA), which condenses with oxaloacetate to form citrate in the tricarboxylic acid (TCA) cycle.…”