Diabetes Metab J.  2018 Aug;42(4):270-281. 10.4093/dmj.2018.0101.

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

• Park S
• Jeon JH
• Min BK
• Ha CM
• Thoudam T
• Park BY
• Lee IK

• KMID: 2418715
• DOI: http://doi.org/10.4093/dmj.2018.0101

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.

Keyword

Glycolysis; Metabolism; Mitochondria; Oxidative phosphorylation

MeSH Terms

Acetylation
Amino Acids
Citric Acid Cycle
Diabetes Mellitus, Type 2
Fatty Acids
Glucose
Glycolysis
Metabolic Diseases
Metabolic Networks and Pathways
Metabolism*
Mitochondria
Neurodegenerative Diseases
Obesity
Oxidative Phosphorylation
Oxidoreductases
Phosphoric Monoester Hydrolases
Phosphorylation
Phosphotransferases
Protein Processing, Post-Translational
Pyruvate Dehydrogenase Complex*
Pyruvic Acid*
Amino Acids
Fatty Acids
Glucose
Oxidoreductases
Phosphoric Monoester Hydrolases
Phosphotransferases
Pyruvate Dehydrogenase Complex
Pyruvic Acid

Figure

• 

  Fig. 1 Dynamic regulations of pyruvate dehydrogenase complex (PDC). Epidermal growth factor (EGF), E3 binding protein (E3BP), free fatty acid (FFA), glucose 6-phosphate (G6P), lactate dehydrogenase (LDH), mitochondrial pyruvate carrier (MPC), oxaloacetate (OAA), pyruvate carboxylase (PC), pyruvate dehydrogenase kinase (PDK), pyruvate dehydrogenase phosphatase (PP), and voltage-dependent anion-selective channel protein (VDAC). ADP, adenosine diphosphate; CoA, coenzyme A; NADH, nicotinamide adenine dinucleotide; ATP, adenosine triphosphate.

• 

  Fig. 2 Hepatic pyruvate dehydrogenase complex (PDC) regulations by pyruvate dehydrogenase kinase (PDK) isozymes. The suggested mechanisms by PDK2 on hepatic steatosis upon a high fat diet (A) and PDK4 on gluconeogenesis by hyperglucagonemia associated with type 2 diabetes mellitus (B). AMP-activated protein kinase (AMPK), cAMP response element binding protein (CREB), cAMP-specific 3′,5′-cyclic phosphodiesterase 4B (PDE4B), diacylglycerol (DAG), free fatty acid (FFA), fatty acid oxidation (FAO), oxaloacetate (OAA), protein kinase A (PKA), pyruvate carboxylase (PC), and PDK. (A) and unpublished data (B). CoA, coenzyme A; TCA, tricarboxylic acid; cAMP, cyclic adenosine monophosphate; ATP, adenosine triphosphate; AMP, adenosine monophosphate; PEPCK, phosphoenolpyruvate carboxykinase; G6Pase, glucose 6-phosphatase.

• 

  Fig. 3 The proposed mechanism of neurological disorders by increased pyruvate dehydrogenase complex (PDC) in astrocyte. Reduced lactic acid by pyruvate dehydrogenase kinase 2/4 (PDK2/4) deficiency resulting in the attenuation of neurological disorders. Glutaminase (GLS), monocarboxylate transporter (MCT), and PDK. CoA, coenzyme A; TCA, tricarboxylic acid.

• 

  Fig. 4 The proposed mechanism of pyruvate dehydrogenase kinase (PDK) as a therapeutic target on kidney dysfunction. Increased PDK4 expression by both high glucose and cisplatin on the apoptosis of renal tubular cells: c-Jun N-terminal kinase (JNK), reactive oxygen species (ROS), and PDK. CoA, coenzyme A; PDC, pyruvate dehydrogenase complex; TCA, tricarboxylic acid; FFA, free fatty acid; FAO, fatty acid oxidation; ATP, adenosine triphosphate.

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