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Chronic Inhibition of Mitochondrial Dihydrolipoamide Dehydrogenase (DLDH) As an Approach to Managing Diabetic Oxidative Stress

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Chronic Inhibition of Mitochondrial Dihydrolipoamide Dehydrogenase (DLDH) As an Approach to Managing Diabetic Oxidative Stress antioxidants Perspective Chronic Inhibition of Mitochondrial Dihydrolipoamide Dehydrogenase (DLDH) as an Approach to Managing Diabetic Oxidative Stress Xiaojuan Yang, Jing Song and Liang-Jun Yan * Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; [email protected] (X.Y.); [email protected] (J.S.) * Correspondence: [email protected]; Tel.: +1-817-735-2386; Fax: +1-817-735-2603 Received: 11 January 2019; Accepted: 28 January 2019; Published: 2 February 2019 Abstract: Mitochondrial dihydrolipoamide dehydrogenase (DLDH) is a redox enzyme involved in decarboxylation of pyruvate to form acetyl-CoA during the cascade of glucose metabolism and mitochondrial adenine triphosphate (ATP) production. Depending on physiological or pathophysiological conditions, DLDH can either enhance or attenuate the production of reactive oxygen species (ROS) and reactive nitrogen species. Recent research in our laboratory has demonstrated that inhibition of DLDH induced antioxidative responses and could serve as a protective approach against oxidative stress in stroke injury. In this perspective article, we postulated that chronic inhibition of DLDH could also attenuate oxidative stress in type 2 diabetes. We discussed DLDH-involving mitochondrial metabolic pathways and metabolic intermediates that could accumulate upon DLDH inhibition and their corresponding roles in abrogating oxidative stress in diabetes. We also discussed a couple of DLDH inhibitors that could be tested in animal models of type 2 diabetes. It is our belief that DLDH inhibition could be a novel approach to fighting type 2 diabetes. Keywords: diabetes mellitus; dihydrolipoamide dehydrogenase; mitochondria; oxidative stress; reactive oxygen species 1. Introduction Adult-onset diabetes mellitus, also known as type 2 diabetes, is caused by insulin resistance followed by β-cell dysfunction [1–3]. The hallmark of this metabolic disorder is persistent hyperglycemia in the blood induced by dysregulation of glucose metabolism [4–6]. While pathogenesis of type 2 diabetes is multifactorial, oxidative stress has been thought to be the converging event leading to development and progression of type 2 diabetes [7–10]. As sources of reactive oxygen species-induced oxidative stress are usually endogenous in type 2 diabetes [11,12], managing diabetic oxidative stress by stimulating endogenous antioxidation pathways may provide a novel approach to fighting diabetes. 2. Oxidative Stress and Diabetes When blood glucose is constantly high, there can be a variety of pathophysiological consequences. These include non-enzymatic modifications of proteins by glucose through a process known as glycation [13–15], elevated levels of reactive oxygen species (ROS) [15,16] that can cause oxidative damage to proteins, DNA, and lipids [17–20], and upregulation of metabolic and signaling pathways that can have detrimental effects on glucose metabolism [21–25]. With respect to elevated ROS Antioxidants 2019, 8, 32; doi:10.3390/antiox8020032 www.mdpi.com/journal/antioxidants Antioxidants 2019, 8, x FOR PEER REVIEW 2 of 9 oxidative damage to proteins, DNA, and lipids [17–20], and upregulation of metabolic and signaling pathways that can have detrimental effects on glucose metabolism [21–25]. With respect to elevated ROS production, it has been established that nearly all the identified pathways that are upregulated by persistent hyperglycemia can induce or contribute to redox imbalance and ROS production [12,26]. TheseAntioxidants include2019, 8, 32the polyol pathway, the protein kinase C activation pathway, the hexosamine2 of 9 pathway, the advanced glycation end products pathway, and the glyceraldehyde autoxidation pathwayproduction, [8,10]. In addition, it has been upregulation established that of nearly the poly all the adenine identified diphosphate pathways that ADP are upregulatedribosylation by pathway and downpersistent regulation hyperglycemia of the sirtuin can induce 3 pathway or contribute have toalso redox been imbalance implicated and ROS in diabetic production oxidative [12,26]. stress These include the polyol pathway, the protein kinase C activation pathway, the hexosamine pathway, that accentuates diabetes and its complications [16,27]. Therefore, we believe that stimulation and the advanced glycation end products pathway, and the glyceraldehyde autoxidation pathway [8,10]. reinforcementIn addition, of cellular upregulation antioxidation of the poly pathways adenine diphosphate are promising ADP ribosylation strategies pathway for attenuating and down diabetic oxidativeregulation stress and of theameliorating sirtuin 3 pathway diabetes. have also been implicated in diabetic oxidative stress that In accentuatesthis article, diabetes we postulate and its complications that chronic [16,27 ].inhibition Therefore, of we believemitochondrial that stimulation dihydrolipomide and dehydrogenasereinforcement (DLDH) of cellular can be antioxidation explored to pathways manage are di promisingabetic oxidative strategies stress for attenuating in diabetic diabetic conditions oxidative stress and ameliorating diabetes. In this article, we postulate that chronic inhibition of mitochondrial dihydrolipomide 3. Mitochondrialdehydrogenase Dihydrolipomide (DLDH) can be explored Dehydrogenase to manage diabetic (DLDH) oxidative stress in diabetic conditions Mitochondrial3. Mitochondrial dihydrolipomide Dihydrolipomide dehydrogenase Dehydrogenase (DLDH)(DLDH) is a flavin adenine dinucleotide (FAD)- containing, nicotinamide adenine dinucleotide (NAD)-dependent disulfide-implicated redox Mitochondrial dihydrolipomide dehydrogenase (DLDH) is a flavin adenine dinucleotide enzyme (FAD)-containing,[28–31]. DLDH nicotinamide participates adenine in three dinucleotide mitochondrial (NAD)-dependent enzyme disulfide-implicatedcomplexes, namely redox pyruvate dehydrogenaseenzyme [complex,28–31]. DLDH α-keto participates glutarate in threedehydrogenase mitochondrial complex, enzyme complexes, and branched namely chain pyruvate amino acid dehydrogenasedehydrogenase complex complex, (Figureα-keto 1). glutarate DLDH dehydrogenaseis also involved complex, in the and glycine branched cleavage chain amino system. acid In the three dehydrogenasedehydrogenase complexcomplexes, (Figure DLDH1). DLDH catalyzes is also involved the same in the reactions glycine cleavage that oxidizes system. dihydrolipoamide In the three to lipoamidedehydrogenase (Figure 2) complexes, so that the DLDH overall catalyzes enzymatic the same reactions reactions can that oxidizescontinue. dihydrolipoamide to lipoamide (Figure2) so that the overall enzymatic reactions can continue. Figure 1. Mitochondrial metabolic pathways involving dihydrolipomide dehydrogenase (DLDH), Figure 1. Mitochondrial metabolic pathways involving dihydrolipomide dehydrogenase (DLDH), which include the pyruvate to acetyl-CoA pathway, the α-ketoglutarate to succinyl-CoA pathway, and which includethe branched the pyruvate chain amino to acidsacetyl-CoA (leucine, isoleucine,pathway, andthe valine) α-ketoglutarate to acyl-CoA pathway.to succinyl-CoA The glycine pathway, and the cleavagebranched pathway chain that amino also involves acids DLDH (leucine, is not shownisoleucine, here. DLDH-involved and valine) complexesto acyl-CoA are indicated pathway. The glycine cleavageby dotted redpathway arrows onthat the also figure. involves BCAA: branched DLDH chain is not amino shown acids; here. NAD+: DLDH-involved nicotinamide adenine complexes α are indicateddinucleotide; by dotted NADH: red reduced arrows form on of the NAD+; figu AAs:re. BCAA: amino acids;branched-KGDC: chain alpha amino ketoglutarate acids; NAD+: dehydrogenase complex; TCA: tricarboxylic acid; BCKA: branched chain keto acid; BCKACD: branched nicotinamidechain alphaadenine keto aciddinucleotide; dehydrogenase NADH: complex; reduced PDC: pyruvate form of dehydrogenase NAD+; AAs: complex. amino acids; α-KGDC: alpha ketoglutarate dehydrogenase complex; TCA: tricarboxylic acid; BCKA: branched chain keto acid; BCKACD: branched chain alpha keto acid dehydrogenase complex; PDC: pyruvate dehydrogenase complex. Antioxidants 2019, 8, x FOR PEER REVIEW 3 of 9 Antioxidants 2019, 8, x FOR PEER REVIEW 3 of 9 Antioxidants 2019, 8, 32 3 of 9 Figure 2.2. TheThe chemicalchemicalreaction reaction catalyzed catalyzed by by DLDH. DLDH. Dihydrolipoamide Dihydrolipoamide is oxidizedis oxidized to lipoamideto lipoamide at the at expensethe expense of NAD+. of NAD+. Hence Hence the DLDH-catalyzed the DLDH-catalyzed reaction reaction produces produces NADH NADH that feeds that into feeds the electroninto the transportelectron transport chain in thechain inner in th mitochondriale inner mitochondrial membrane. membrane. Figure 2. The chemical reaction catalyzed by DLDH. Dihydrolipoamide is oxidized to lipoamide at DLDH is a multifunctional protein. In rat, the brain and the testis appear to have the highest theDLDH expense is aof multifunctional NAD+. Hence the protein. DLDH-catalyzed In rat, the reactionbrain and produces the testis NADH appear that tofeeds have into the the highest DLDH activity while the lung gives the lowest DLDH activity [31]. When it exists as a homodimer in DLDHelectron activity transport while chain the lung in th egives inner the mitochondrial lowest DLDH membrane. activity [31]. When it exists as a homodimer in the above mentioned dehydrogenase complexes, it is a classical redox-dependent enzyme that converts the above mentioned
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