Biomedical Research and Therapy, 7(2):3645-3658 Open Access Full Text Article Review Emerging regulatory roles of mitochondrial sirtuins on pyruvate dehydrogenase complex and the related metabolic diseases: Review Abolfazl Nasiri1,2, Masoud Sadeghi3, Asad Vaisi-Raygani2,4, Sara Kiani3, Zahra Aghelan1,2, Reza Khodarahmi3,5,* ABSTRACT The pyruvate dehydrogenase complex (PDC) is a multi-enzyme complex of the mitochondria that provides a link between glycolysis and the Krebs cycle. PDC plays an essential role in producing Use your smartphone to scan this acetyl-CoA from glucose and the regulation of fuel consumption. In general, PDC enzyme is reg- QR code and download this article ulated in two different ways, end-product inhibition and posttranslational modifications (moreex- tensive phosphorylation and dephosphorylation subunit E1). Posttranslational modifications of this enzyme are regulated by various factors. Sirtuins are the class III of histone deacylatases that catalyze 1Students Research Committee, protein posttranslational modifications, including deacetylation, adenosine diphosphate ribosyla- Kermanshah University of Medical tion, and deacylation. Sirt3, Sirt4, and Sirt5 are mitochondrial sirtuins that control the posttrans- Sciences, Kermanshah, Iran lational modifications of mitochondrial protein. Considering the comprehensive role of sirtuins in post-translational modifications and regulation of metabolic processes, the aim of this review isto 2 Department of Clinical Biochemistry, explore the role of mitochondrial sirtuins in the regulation of the PDC. PDC deficiency is a com- School of Medicine, Kermanshah mon metabolic disorder that causes pyruvate to be converted to lactate and alanine rather than to University of Medical Sciences, Kermanshah, Iran acetyl-CoA. because this enzyme is in the gateway of complete oxidation, glucose products enter- ing the Krebs cycle and resulting in physiological and structural changes in the organs. Metabolic 3Medical Biology Research Center, blockage such as ketogenic diet broken up by b-oxidation and producing acetyl-CoA can improve Kermanshah University of Medical the patients. Sirtuins play a role in the production of acetyl-CoA through oxidation of fatty acids Sciences, Kermanshah, Iran and other pathways. Thus, we hypothesize that the targets and bioactive compounds targeting 4Fertility and Infertility Research Center, mitochondrial sirtuins can be involved in the treatment of PDC deficiency. In general, this review Health Technology Institute, discusses the present knowledge on how mitochondrial sirtuins are involved in the regulation of Kermanshah University of Medical PDC as well as their possible roles in the treatment of PDC deficiency. Sciences, Kermanshah, Iran Key words: Pyruvate dehydrogenase complex deficiency, Mitochondrial Sirtuins, protein deacety- 5Department of Pharmacognosy and lation Biotechnology, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran INTRODUCTION enzymes have an important role in all mitochon- Correspondence The human pyruvate dehydrogenase (PD) is a multi- dria of higher eukaryotes. This complex is active in Reza Khodarahmi, Medical Biology aerobic conditions that require glucose decomposi- Research Center, Kermanshah University enzyme complex that is involved in the produc- of Medical Sciences, Kermanshah, Iran tion of nicotinamide adenine dinucleotide dehydro- tion to produce energy, and is suppressed when glu- Department of Pharmacognosy and genase (NADH), carbon dioxide (CO2), and acetyl- cose is in short supply. In general, this enzyme is Biotechnology, Faculty of Pharmacy, coenzyme A (CoA) by pyruvate decarboxylation. The regulated in two different ways, end-product inhi- Kermanshah University of Medical bition by acetyl CoA and NADH 12 and phospho- Sciences, Kermanshah, Iran common pyruvate dehydrogenase complex (PDC) has three main enzymes and five coenzymes 1–7. The rylation and dephosphorylation subunit E1, which Email: [email protected] are a non-phosphorylated active form and a phos- History three components enzymes PDC include pyruvate • Received: Aug 06, 2019 dehydrogenase (E1, a heterotetramer of two types, phorylated inactive form. However, its regulation • Accepted: Dec 23, 2019 with EC 1.2.4.1), dihydrolipoamide acetyltransferase is not fully understood. PDC deficiency is a mito- • Published: Feb 29, 2019 (E2, EC 2.3.1.12) and dihydrolipoamide dehydroge- chondrial defect, whose gene is encoded in the nu- DOI : 10.15419/bmrat.v7i2.591 nase (E3, EC 1.8.1.4,) 8,9. E3 binding protein (E3BP) cleus and the most identified motive over neonatal en- is an additional subunit that exists in humans, and cephalopathies with primary lactic acidosis 13. PDC integrates stable E3 into the E2 core of each assem- deficiency may be triggered by the defects of E1a, Copyright bly 9–11. Each assembly consists of five coenzymes, E1b, E2, or E3 subunits. This deficiency is often due © Biomedpress. This is an open- including thiamine pyrophosphat, lipoic acid, CoA, to alteration in the E1 gene located on X chromo- access article distributed under the flavin adenine dinucleotide, and nicotinamide ade- some; all other causes are due to defects in recessive terms of the Creative Commons + 14–16 Attribution 4.0 International license. nine dinucleotide (NAD ). PDC and its regulatory genes . Several strategies have been reported to Cite this article : Nasiri A, Sadeghi M, Vaisi-Raygani A, Kiani S, Aghelan Z, Khodarahmi R. Emerging regula- tory roles of mitochondrial sirtuins on pyruvate dehydrogenase complex and the related metabolic diseases: Review. Biomed. Res. Ther.; 7(2):3645-3658. 3645 Biomedical Research and Therapy, 7(2):3645-3658 be useful in the treatment of PDC deficiency. These processes, generally through posttranslational modi- encompass the use of ketogenic diets (KD), adminis- fications 33,34. Posttranslational modifications are in- tration of dichloroacetate and thiamine supplements. volved in the regulation of PDC, but their regula- Unfortunately, none of these is generalized 14–16 . tion is not well-defined. Considering the comprehen- Sirtuins are protected enzymes in most species, in- sive role of sirtuins in post-translational modifications cluding humans and bacteria. They rely on NAD+ for and the regulation of metabolic processes, this review their reaction (Figure 1). Recently, it has been ob- was conducted to determine whether sirtuins are in- served that sirtuins can catalyze reactions including volved in the regulation of PDC or not. Deficiency deacetylation, adenosine diphosphate (ADP) ribosy- of PDC causes pyruvate to be converted into lactate 17 lation, and deacylation . The mammalian deacety- and alanine instead of acetyl-CoA because this en- lases are divided into four classes I, II, III, and IV, zyme is in the gateway of complete oxidation of glu- 18 based on sequence homology . Classes I, II, and IV cose products entering the Krebs cycle. Metabolic mammalian deacetylases include enzymes that con- blockage such as ketogenic diet is broken up by b- tain zinc as a cofactor in their structure. The zinc co- oxidation, and production of acetyl-CoA can improve factor plays a role in activating water molecules as a the condition. The therapies used for the treatment nucleophile and hydrolysis of the acetamide bond in of this deficiency have not been fully successful. Sir- e 19 acetate and lysine -amino group . Class III mam- tuins are involved in the production of acetyl-CoA malian deacetylase proteins, which are called sirtuins, through oxidation of fatty acids and other pathway have zinc molecules in their structure; however, the complexes. Thus, pharmacological targets and bioac- zinc elements are not directly involved in the reac- tive compounds targeting mitochondrial sirtuins can tion. Instead, Sirtuins utilize nicotinamide adenine be involved in the treatment of PDC deficiency. This + dinucleotide (NAD ) cosubstrate as a cofactor to pro- review discusses the present knowledge on how mito- duce ADP-ribose as a nucleophile 20. ADP-ribose re- chondrial sirtuins is involved in the regulation of PDC mains for ADP-ribosylation of the substrate, alter- as well as their possible roles in the treatment of PDC natively on deacetylation, but this reaction is likely deficiency. to stay aside response 21. In mammals, seven sirtu- ins have been discovered, ranging from Sirt1 to Sirt7. PDC AND ITS REGULATORY Sirt1 and Sirt2 are present both in the nucleus and in FACTORS the cytoplasm, while Sirt6 and Sirt7 are only seen in PDC catalyzes the oxidative decarboxylation reaction the nucleus. Sirt3, Sirt4, and Sirt5 are known as mi- of pyruvate to acetyl-CoA. The function of this en- tochondrial Sirtuins (Figure 2) 22. Based on phylo- genetic conservation of the core domain, sirtuins are zyme is irreversible and has a regulatory role in the categorized into five subclasses (I–IV and U). Subclass entry of glucose products into mitochondria. This en- I contains Sirt1, Sirt2, and Sirt3 with deacetylase ac- zyme interlinks glycolysis to the Krebs cycle, and sub- tivity. Subclass II sirtuins include Sirt4, which exhibits sequently to the respiratory chain, therefore, it can be ADP-ribosyltransferase activity 23,24. Subclass III sir- an important for the synthesis of adenosine triphos- tuins include Sirt5 that exhibits deacylase activity 25 phate (ATP) by the transfer of electrons (NADH, 35 and weak deacetylase activity 26. Subclass IV sirtu- FADH) to the respiratory chain . In lipogenic tis- ins contains Sirt6