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

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.

SUBMITTER: Yang X

PROVIDER: S-EPMC6406859 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Yang Xiaojuan X Song Jing J Yan Liang-Jun LJ

Antioxidants (Basel, Switzerland) 20190202 2

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 ...[more]

PMID: 30717346

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Project description:Under oxidative stress conditions, mitochondria are the major site for cellular production of reactive oxygen species (ROS) such as superoxide anion and H2O2 that can attack numerous mitochondrial proteins including dihydrolipoamide dehydrogenase (DLDH). While DLDH is known to be vulnerable to oxidative inactivation, the mechanisms have not been clearly elucidated. The present study was therefore designed to investigate the mechanisms of DLDH oxidative inactivation by mitochondrial reactive oxygen species (ROS). Mitochondria, isolated from rat brain, were incubated with mitochondrial respiratory substrates such as pyruvate/malate or succinate in the presence of electron transport chain inhibitors such as rotenone or antimycin A. This is followed by enzyme activity assay and gel-based proteomic analysis. The present study also examined whether ROS-induced DLDH oxidative inactivation could be reversed by reducing reagents such as DTT, cysteine, and glutathione. Results show that DLDH could only be inactivated by complex III- but not complex I-derived ROS; and the accompanying loss of activity due to the inactivation could be restored by cysteine and glutathione, indicating that DLDH oxidative inactivation by complex III-derived ROS was a reversible process. Further studies using catalase indicate that it was H2O2 instead of superoxide anion that was responsible for DLDH inactivation. Moreover, using sulfenic acid-specific labeling techniques in conjunction with two-dimensional Western blot analysis, we show that protein sulfenic acid formation (also known as sulfenation) was associated with the loss of DLDH enzymatic activity observed under our experimental conditions. Additionally, such oxidative modification was shown to be associated with preventing DLDH from further inactivation by the thiol-reactive reagent N-ethylmaleimide. Taken together, the present study provides insights into the mechanisms of DLDH oxidative inactivation by mitochondrial H2O2.

Project description:Aim: Sirtuin3 (sirt3) plays a pivotal role in improving oxidative stress and mitochondrial dysfunction which directly induced neuronal apoptosis after intracerebral hemorrhage (ICH). Reactive oxygen species (ROS) is also a critical activator in triggering NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasomes activation which can regulate inflammatory responses in brain. Moreover, hyperglycemia can aggravate the ICH-induced damage. Hence, this study was designed to investigate the mechanisms of neuroprotection of sirt3 in hyperglycemic ICH. Methods: ICH model was established by autologous blood injection. Hyperglycemia was induced by intraperitoneal injection with streptozotocin. Honokiol (HKL, a pharmacological agonist of sirt3) was injected intraperitoneally at doses of 2.5, 5, or 10 mg/kg. Sirt3 small interfering RNA transfection was implemented through intracerebroventricular injection. The expression of sirt3 and its downstream signaling molecules were detected using Western blotting or immunofluorescence staining. Morphological changes of mitochondria were detected by electron microscopy. SH-SY5Y cells were incubated with 10 ?M oxyhemoglobin for 48 h to establish an in vitro ICH model, and then JC-1 staining was used to determine mitochondrial membrane potential (??m). Results: Hyperglycemia could suppress sirt3 expression after ICH when compared with non-diabetic rats. Sirt3 protein expression was decreased to the minimum at 24 h in perihematoma tissues. Electron microscope analysis indicated that hyperglycemic ICH induced extensive mitochondrial vacuolization. HKL attenuated ROS accumulation, adenosine triphosphate reduction, and ??m through Sirt3-superoxide dismutase 2 (SOD2) and Sirt3-NRF1-TFAM pathway. Sirt3 knockdown could exacerbate the neuronal apoptosis and reverse the positive effects of HKL. Sirt3 activation could decrease NLRP3 and interleukin-1? levels through deacetylating SOD2 and scavenging ROS. Conclusion: HKL protects against hyperglycemic ICH-induced neuronal injury via a sirt3-dependent manner.

Dataset Information

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

Publications

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

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