Targeting nucleotide-requiring enzymes: implications for diazoxide-induced cardioprotection

Dzeja, Petras P.; Bast, Peter; Özcan, Cevher; Valverde, Arturo M.; Holmuhamedov, Ekshon L.; Wylen, D. G. L. Van; Terzic, André

doi:10.1152/ajpheart.00847.2002

Cited by 101 publications

(126 citation statements)

References 72 publications

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“…In addition, mitochondrial swelling could play a role in triggering of apoptosis via volume-depedent cytochrome c releasing (Gogvadze et al 2004). Changes in mitochondrial matrix volume homeostasis could be linked to ROS production, but there is heterogeneity of results (Carroll et al 2001;Dzeja et al 2003). Our study did not prove any significant changes in ROS production in α-mannosidosis fibroblasts compared to control cell lines.…”

Section: Discussioncontrasting

confidence: 60%

Ultrastructural and functional abnormalities of mitochondria in cultivated fibroblasts from α-mannosidosis patients

et al. 2009

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α-Mannosidosis is a lysosomal storage disorder caused by α-mannosidase deficiency. Clinical course of the disease ranges from severe infantile to milder juvenile type and includes mental retardation, skeletal deformities, coarse facies, hepatomegaly and hearing loss. The aim of the study was to analyse mitochondrial ultrastructure and function in cultivated fibroblasts from three patients with α-mannosidosis. All patients were homozygous for the c.2248C>T mutation in the MAN2B1 gene encoding lysosomal α-mannosidase. The mutation results in incorrect protein folding and severe decrease of α-mannosidase activity. The misfolded protein is retained by the control system of endoplasmic reticulum (ER). In analysed fibroblasts, we observed dilated ER, higher amount of aberrant mitochondria and reduced mitochondrial mass compared to controls. Respiratory chain complex IV, cytochrome c oxidase (COX), activity and the ratio between COX and citrate synthase (control enzyme) were significantly increased in comparison to controls (P < 0.05). Furthermore, the activity at least from one of other respiratory chain complexes was increased in each studied cell line. Mitochondrial membrane potential as well as reactive oxygen species production were comparable with controls. Based on our results, we hypothesize more profound effect of swelled and damaged mitochondria and ER dilatation on tissues with higher energy demand than fibroblasts have.

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Section: Discussioncontrasting

confidence: 60%

Ultrastructural and functional abnormalities of mitochondria in cultivated fibroblasts from α-mannosidosis patients

et al. 2009

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“…Succinate dehydrogenase. The activity of succinate dehydrogenase (SDH), an index of metabolic capacity, was determined by spectrophotometry in whole-tissue homogenates of hamstring muscle groups (34). The assay mixture contained 66.7 mmol/l Tris ⅐ HCl buffer (pH 8), 6.67 mmol/l KCN, 420 mol/l phenazine methosulfonate, and 86 mol/l 2,6-dichloroindophenol (DCIP), 1 mol/l rotenone, and 10 mg/ml skeletal muscle extract.…”

Section: Methodsmentioning

confidence: 99%

ATP-Sensitive K+ Channel Knockout Compromises the Metabolic Benefit of Exercise Training, Resulting in Cardiac Deficits

Kane

Behfar²,

Yamada³

et al. 2004

Diabetes

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109

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Exercise training elicits a metabolic and cardiovascular response that underlies fitness. The molecular mechanisms that orchestrate this adaptive response and secure the wide-ranging gains of a regimented exercise program are poorly understood. Formed through association of the Kir6.2 pore and the sulfonylurea receptor, the stress-responsive ATP-sensitive K ؉ channels (K ATP channels), with their metabolic-sensing capability and broad tissue expression, are potential candidates for integrating the systemic adaptive response to repetitive exercise. Here, the responses of mice lacking functional Kir6.2-containing K ATP channels (Kir6.2-KO) were compared with wild-type controls following a 28-day endurance swimming protocol. While chronic aquatic training resulted in lighter, leaner, and fitter wild-type animals, the Kir6.2-KO manifested less augmentation in exercise capacity and lacked metabolic improvement in body fat composition and glycemic handling with myocellular defects. Moreover, the repetitive stress of swimming unmasked a survival disadvantage in the Kir6.2-KO, associated with pathologic calcium-dependent structural damage in the heart and impaired cardiac performance. Thus, Kir6.2-containing K ATP channel activity is required for attainment of the physiologic benefits of exercise training without injury. Diabetes 53 (Suppl. 3): S169 -S175, 2004 P hysical exertion elicits an array of metabolic and cardiovascular responses that allow the body to adapt to the demands of exercise, thereby achieving fitness, a state of enhanced aerobic capacity, and generalized well-being (1-4). Reinforced by frequent repetition of the exercise regimen, the specific systemic benefits of regular activity range from reductions in body weight and adiposity to improved glucose and insulin homeostasis (1-7). Moreover, the inverse relation of physical exercise with both cardiovascular disease and mortality has long been recognized (1,4,8,9). Yet, the molecular determinants that orchestrate the adaptive response to exercise and that assure the wide-ranging gains of a regimented training program are poorly understood.Unique metabolic-sensing capabilities and broad tissue expression point to the ATP-sensitive K ϩ channel (K ATP channel) as a potential candidate for integrating the systemic adaptive response and thereby securing the benefits of exercise training. K ATP channels are evolutionarily conserved plasma-membrane protein complexes, widely represented in tissue beds with high metabolic activity (10 -14). There, they are formed through the physical association of the inwardly rectifying potassium channel pore, most typically Kir6.2, and the regulatory sulfonylurea receptor subunit, an ATP-binding cassette protein (15)(16)(17). Energetic signals, received via tight integration with cellular metabolic pathways, are processed by the sulfonylurea receptor subunit that in turn gates the nucleotide sensitivity of the channel pore, thereby controlling membrane potential-dependent cellular functions (18 -21). Recent findings, elicited ...

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“…The ability of DZ to bind to ATP-binding proteins implies multiple nonspecific targets of this drug with several ensuing off-target effects affecting mitochondrial functions and bioenergetics. Indeed, the interaction of DZ with F 0 F 1 ATP synthase [15,18,19], Ca 2+ , Mg 2+ -ATPase(s) [19], and ADP/ATP carrier (ANT) [57] was shown. Other well-known targets of DZ are succinate dehydrogenase (SDH) [15][16][17] and protein kinases, especially protein kinase C epsilon [2,21,22].…”

Section: Nonspecific Cellular Targets Of Diazoxidementioning

confidence: 99%

“…Indeed, the interaction of DZ with F 0 F 1 ATP synthase [15,18,19], Ca 2+ , Mg 2+ -ATPase(s) [19], and ADP/ATP carrier (ANT) [57] was shown. Other well-known targets of DZ are succinate dehydrogenase (SDH) [15][16][17] and protein kinases, especially protein kinase C epsilon [2,21,22]. F 0 F 1 ATP synthase: In several works down modulation of F 0 F 1 ATP synthase activity by DZ, either resulting [18,58], or not resulting from mK ATP channel opening [15,19] was reported.…”

Section: Nonspecific Cellular Targets Of Diazoxidementioning

confidence: 99%

“…Being a highly hydrophobic compound, DZ easily binds to and penetrates cellular membranes [12]. This ability implies several cellular targets of DZ, and thus far several side effects of DZ on mitochondrial functions have been reported, such as protonophoric properties at high micromolar concentrations [13,14]; inhibition of succinate dehydrogenase (SDH) and succinatedriven respiration [15][16][17]; inhibition of F 0 F 1 ATP synthase [18,19]; flavoprotein oxidation and the interference with ROS detection using the fluorescent probe Dichlorofluorescein (DCF) [16,20]; at last, direct activation of protein kinases (C and B) and other signaling pathways [2,21,22].…”

Section: Introductionmentioning

confidence: 99%

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Direct and Off-Target Effects of ATP-Sensitive Potassium Channels Opener Diazoxide

Акопова¹

2017

J Drug Metab Toxicol

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Diazoxide (DZ) is a well-known cardioprotective drug capable of mimicking ischemic preconditioning. Being primarily a pharmacological opener of mitochondrial ATP-sensitive potassium channels (mK ATP channels), DZ is known to produce multiple side effects because of its interactions with different cellular targets (such as plasma membrane K ATP channels, F 0 F 1 ATP synthase, succinate dehydrogenase and others), capable of confounding an understanding of direct bioenergetic effects of mK ATP channels opening in mitochondria. In this review direct and offtarget effects of DZ were discussed. The emphasis was made on molecular basis of DZ interaction with K ATP channels and different K ATP channels isoforms sensitivity to this drug. The present knowledge on DZ interaction with mK ATP channels is outlined as well as DZ interactions with other molecular targets affecting mitochondrial functions and bioenergetics. Conclusion was reached that high sensitivity of mK ATP channel to DZ allows for avoiding offtarget effects of this drug in studies on isolated mitochondria, which makes it a useful tool in an appraisal of diverse functional effects of mK ATP channel opening.

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Targeting nucleotide-requiring enzymes: implications for diazoxide-induced cardioprotection

Cited by 101 publications

References 72 publications

Ultrastructural and functional abnormalities of mitochondria in cultivated fibroblasts from α-mannosidosis patients

Ultrastructural and functional abnormalities of mitochondria in cultivated fibroblasts from α-mannosidosis patients

ATP-Sensitive K+ Channel Knockout Compromises the Metabolic Benefit of Exercise Training, Resulting in Cardiac Deficits

Direct and Off-Target Effects of ATP-Sensitive Potassium Channels Opener Diazoxide

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