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

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Role of the Pyruvate Dehydrogenase Complex in Metabolic Remodeling: Differential Pyruvate Dehydrogenase Complex Functions in Metabolism Review Obesity and Metabolic Syndrome Diabetes Metab J 2018;42:270-281 https://doi.org/10.4093/dmj.2018.0101 pISSN 2233-6079 · eISSN 2233-6087 DIABETES & METABOLISM JOURNAL Role of the Pyruvate Dehydrogenase Complex in Metabolic Remodeling: Differential Pyruvate Dehydrogenase Complex Functions in Metabolism Sungmi Park1, Jae-Han Jeon2, Byong-Keol Min3, Chae-Myeong Ha3, Themis Thoudam3, Bo-Yoon Park3, In-Kyu Lee1,2,3 1Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, 2Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, 3Department of Biomedical Science & BK21 plus KNU Biomedical Convergence Programs, Kyungpook National University, Daegu, Korea Mitochondrial dysfunction is a hallmark of metabolic diseases such as obesity, type 2 diabetes mellitus, neurodegenerative diseas- es, 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, in- cluding 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 var- ious metabolic disorders. Keywords: Glycolysis; Metabolism; Mitochondria; Oxidative phosphorylation INTRODUCTION strate of PDC, can be utilized for the citric acid cycle after gly- colysis or be converted into glucose, glycerol, fatty acids, and It has been well established that attenuated mitochondrial oxi- non-essential amino acids. This is determined by (1) the effi- dative phosphorylation and cellular respiration is associated ciency of the mitochondrial pyruvate carrier, (2) the inhibitory with age-related diseases such as obesity, diabetes, neurological effect of pyruvate dehydrogenase kinase (PDK) on PDC, or (3) disorders including Alzheimer’s and Parkinson’s diseases, and an alternative pathway where the pyruvate carboxylase (PC) proliferative cancers. The mitochondrial pyruvate dehydroge- activity is correlated with the rate of gluconeogenesis [2]. nase complex (PDC) has been implicated as a potential thera- The concept of “metabolic inflexibility” describes the failure peutic target because of its activity as a key modulator of ener- of metabolism in insulin-resistant human subjects who are not gy and metabolic homeostasis [1]. Pyruvate, the primary sub- able to respond appropriately to nutritional cues, in terms of Corresponding authors: In-Kyu Lee https://orcid.org/0000-0002-2261-7269 This is an Open Access article distributed under the terms of the Creative Commons Department of Internal Medicine, School of Medicine, Kyungpook National University, Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) 130 Dongdeok-ro, Jung-gu, Daegu 41944, Korea which permits unrestricted non-commercial use, distribution, and reproduction in any E-mail: [email protected] medium, provided the original work is properly cited. Sungmi Park https://orcid.org/0000-0002-3074-5914 Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, 807 Hoguk-ro, Buk-gu, Daegu 41404, Korea E-mail: [email protected] Received: Jun. 17, 2018; Accepted: Jul. 5, 2018 Copyright © 2018 Korean Diabetes Association http://e-dmj.org Dynamic PDH regulations in metabolism adjusting fuel oxidation. Hence, the efflux of acetyl-coenzyme obesity, diabetes, heart failure, and cancer, and upregulated A (CoA) from excess β-oxidation via carnitine acetyltransfer- PDK2 is a potential target for improving glucose tolerance and ase restores insulin function by countering the inhibitory effect reducing hepatic steatosis [10]. Many approaches to improve on PDC [3]. Many preclinical studies have highlighted the PDC activity have been tested using various PDK inhibitors. beneficial effect of using dichloroacetate (DCA) in combina- However, a deeper understanding of various regulatory factors tion therapy when tumor resistance has developed to standard on PDC activity is still required to design novel targets for nu- platinum-class drugs alone, which mediates the redirection of merous metabolic diseases. glucose metabolism from lactate production to complete oxi- dation followed by the induction of caspase-mediated apopto- TRANSLATIONAL APPROACH THROUGH sis [4]. The multifunctional PDC regulates metabolic repro- ACETYLATION AND SUCCINYLATION gramming involved in pyruvate metabolism to maintain ho- meostasis and survival. Additionally, the existence of nuclear Protein posttranslational modifications play an important role PDC highlights the complexity of mitochondrial PDC regula- in regulating cellular processes. These modifications include tion beyond cellular respiration [5]. Hence, this review sum- acetylation, methylation, biotinylation, ubiquitination, butyry- marizes the recent findings on PDC regulation in differential lation, propionylation, crotonylation, malonylation, and succi- tissues and the metabolic flux following the modulated PDC nylation, which can be identified with the help of high-resolu- activities in diverse metabolic environments. tion mass spectrometry [11]. Lysine residues in particular are targets for many posttranslational modifications like acetyla- REVERSIBLE PHOSPHORYLATION BY PDK tion and succinylation, which are abundantly identified and AND PDP studied in different PDC components for their involvement in energy metabolism [12]. According to protein complex analy- PDK 1-4 which are serine-specific kinases ranging from 45 to sis of the Lys succinylation proteome, sirtuin 5 (SIRT5) directly 48 kDa are the main players that phosphorylate and inactivate and negatively regulates PDH E1α by de-succinylation [11]. A pyruvate dehydrogenase (PDH) E1α. PDK2 exhibits the high- high NADH/NAD+ ratio and acetyl-CoA/CoA ratio causes a est phosphorylation activity on Ser293 of PDH E1α, followed reduction in the number of lipoyl groups on the dihydroli- by PDK4, PDK1, and then PDK3 [6]. However, Ser232 is spe- poamide dehydrogenase subunit (E3) and promotes the acety- cifically phosphorylated by PDK1 under acidic conditions re- lation of the reduced lipoyl groups by the dihydrolipoamide sulting from the excessive production of acidic metabolites in- acetyltransferase subunit (E2) [13]. cluding lactate, protons, and CO2 through increased glycolysis Mitochondrial acetylation levels are counter-regulated by and glutaminolysis [7]. The hypoxia-inducible factor-1α acetyl-CoA acetyltransferase 1 (ACAT1) and SIRT3 as the up- (HIF1α)-mediated PDK1 overexpression reduces the oxida- stream acetyltransferase and deacetylase, respectively. The en- tion of glucose and glutamine while increasing the reductive zymes act on both PDH E1α at K321 and PDP1 at K202, re- isocitrate dehydrogenase flux, causing reductive carboxylation sulting in the recruitment of PDK1 and the dissociation of of glutamine into citrate for proliferation, which suggests met- PDP1 from PDH E1α. They are separately dependent on the abolic reprogramming [8]. level of acetyl-CoA and succinyl-CoA, and both can be re- The kinetic activity of PDK is stimulated rapidly by adenos- versed by members of the SIRT family [14]. Large-scale quan- ine triphosphate (ATP), nicotinamide adenine dinucleotide titative analysis of the global proteome, acetylome, and succi- (NADH), and acetyl-CoA, and is inhibited by adenosine di- nylome using high sensitivity mass spectrometry and bioinfor- phosphate (ADP), NAD+, coenzyme A-SH, and pyruvate in a matics demonstrates that both acetylation and succinylation by-product feedback inhibition manner [7]. The Ca2+-sensitive affect specific enzymes of central carbon metabolism including isoform (pyruvate dehydrogenase phosphatase 1 [PDP1]) is PDH, mediated by the anti-tumoral effect of DCA [15]. Based highly expressed in rat heart, brain, and testis, but only the on the growing data set of acetylation and succinylation in var- Ca2+-insensitive isoform (PDP2) is regulated by starvation, in ious proteins, modification of residues on PDC should be as- the heart [9]. sessed to show their significance in the overall function. PDK isoforms are increased in metabolic diseases including http://e-dmj.org Diabetes Metab J 2018;42:270-281 271 Park S, et al. REGULATORY METABOLITES activated receptor α (PPARα)- or retinoid X receptor (RXR)- induced PDK4 expression is mostly responsive to the in- The higher levels of reactive molecular species including meta- creased NADH/NAD+ ratios from mitochondrial β-oxidation bolic intermediates (acetyl-CoA and succinyl-CoA) and reac- [19]. Glucose is utilized not only to generate ATP by glycolysis, tive oxygen species (ROS) can modulate enzymatic activities but also as a building block for other macromolecule biosyn- involved in the glycolytic pathway
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