Relationships between human vitality and mitochondrial respiratory parameters, reactive oxygen species production and dNTP levels in peripheral blood mononuclear cells

Maynard, Scott; Keijzers, Guido; Gram, Martin; Desler, Claus; Bendix, Laila; Budtz-Jørgensen, Esben; Molbo, Drude; Croteau, Deborah L.; Osler, Merete; Stevnsner, Tinna; Rasmussen, Lene Juel; Dela, Flemming; Avlund, Kirsten; Bohr, Vilhelm A.

doi:10.18632/aging.100618

Cited by 32 publications

(30 citation statements)

References 51 publications

(74 reference statements)

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“…In light of this, the observed decrease in ATP production driven by DNP treatment may be inhibiting the activity of the ATP-dependent proton pumps, thereby altering the pH or ion gradients and ultimately driving the lower non-mitochondrial respiration we document. In addition, levels of non-mitochondrial oxidase activity have also been linked to mitochondrial ROS production, (Maynard et al, 2013), an observation in line with our data indicating decreased ROS production as a result of DNP treatment (see below). Despite the decrease in mitochondrial ATP output, at 24 hpf the total organismal ATP content of DNP-treated embryos was not different from control embryos (Fig.…”

Section: Discussionsupporting

confidence: 90%

The cellular and molecular progression of mitochondrial dysfunction induced by 2,4-dinitrophenol in developing zebrafish embryos

et al. 2015

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The etiology of mitochondrial disease is poorly understood. Furthermore, treatment options are limited, and diagnostic methods often lack the sensitivity to detect disease in its early stages. Disrupted oxidative phosphorylation (OXPHOS) that inhibits ATP production is a common phenotype of mitochondrial disorders that can be induced in zebrafish by exposure to 2,4-dinitrophenol (DNP), a FDA-banned weight-loss agent and EPA-regulated environmental toxicant, traditionally used in research labs as an uncoupler of OXPHOS. Despite the DNP-induced OXPHOS inhibition we observed using in vivo respirometry, the development of the DNP-treated and control zebrafish were largely similar during the first half of embryogenesis. During this period, DNP-treated embryos induced gene expression of mitochondrial and nuclear genes that stimulated the production of new mitochondria and increased glycolysis to yield normal levels of ATP. DNP-treated embryos were incapable of sustaining this mitochondrial biogenic response past mid-embryogenesis, as shown by significantly lowered ATP production and ATP levels, decreased gene expression, and the onset of developmental defects. Examining neural tissues commonly affected by mitochondrial disease, we found that DNP exposure also inhibited motor neuron axon arbor outgrowth and the proper formation of the retina. We observed and quantified the molecular and physiological progression of mitochondrial dysfunction during development with this new model of OXPHOS dysfunction, which has great potential for use in diagnostics and therapies for mitochondrial disease.

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Section: Discussionsupporting

confidence: 90%

The cellular and molecular progression of mitochondrial dysfunction induced by 2,4-dinitrophenol in developing zebrafish embryos

et al. 2015

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“…Bioenergetic dysfunction has been demonstrated in various disease states including Alzheimer's disease [37], type 2 diabetes [38] and anorexia nervosa [39]. Each of these disorders has also been associated with low vitamin D status [40], [41], [42].…”

Section: Discussionmentioning

confidence: 99%

Prevailing vitamin D status influences mitochondrial and glycolytic bioenergetics in peripheral blood mononuclear cells obtained from adults

et al. 2016

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BackgroundCirculating peripheral blood mononuclear cells (PBMCs) are exposed to metabolic and immunological stimuli that influence their functionality. We hypothesized that prevailing vitamin D status [25(OH)D] would modulate the bioenergetic profile of PBMCs derived from humans.Materials and methods38 participants (16 males, 22 females) ranging in body fat from 14–51% were studied. PBMCs were isolated from whole blood, counted and freshly seeded for bioenergetic analysis using the Seahorse XFe96 flux analyser. Whole body energy metabolism via indirect calorimetry, body composition by dual-energy X-ray absorptiometry, and relevant clinical biochemistry were measured. Data was analysed based on 25(OH)D cut-offs of <50 nmol/L (Group 1, n=12), 50–75 nmol/L (Group 2, n=15) and ≥75 nmol/L (Group 3, n=11). A multivariate general linear model adjusting for age, fat mass, fat-free mass, parathyroid hormone and insulin sensitivity was used.ResultsThere were significant differences in cellular mitochondrial function between groups. Group 1 had significantly higher basal respiration (p=0.001), non-mitochondrial respiration (p=0.009), ATP production (p=0.001), proton leak (p=0.018), background glycolysis (p=0.023) and glycolytic reserve (p=0.039) relative to either Group 2 or Group 3; the latter two did not differ on any measures. There were no differences in bioenergetic health index (BHI), resting metabolic rates and systemic inflammatory markers between groups.ConclusionsInadequate vitamin D status adversely influenced bioenergetic parameters of PBMCs obtained from adults, in a pattern consistent with increased oxidative metabolism and activation of these cells.

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“…57 The dual function of 2-AG should be taken into account, especially considering that platelet hyperactivation is related to aging, inflammation and cancer. 58,59 Age-related decline in cardiovascular function (and, therefore, susceptibility to thrombotic and inflammatory disorders) is often associated to increased levels of reactive oxygen species and oxidative stress; 60,61 since aged platelets display increased NADPH oxidase expression and hydrogen peroxide generation, platelet hyperactivity may contribute to this phenomenon. 62 Aging and activated platelets also modulate lineage-specific development, as well as the senescence program itself, thus promoting cell transformation and playing a role in the early progression to malignancy; [63][64][65][66] in particular, by shedding micro-RNA-containing microvesicles, activated platelets may have clinical relevance in promoting tumor growth and spread, 67 and potentially could be used as biomarkers, as circulating micro-RNA-containing microvesicles may differ according to cancer stage.…”

Section: Discussionmentioning

confidence: 99%

2-Arachidonoylglycerol enhances platelet formation from human megakaryoblasts

et al. 2014

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Platelets modulate vascular system integrity, and their loss is critical in haematological pathologies and after chemotherapy. Therefore, identification of molecules enhancing platelet production would be useful to counteract thrombocytopenia. We have previously shown that 2-arachidonoylglycerol (2-AG) acts as a true agonist of platelets, as well as it commits erythroid precursors toward the megakaryocytic lineage. Against this background, we sought to further interrogate the role of 2-AG in megakaryocyte/platelet physiology by investigating terminal differentiation, and subsequent thrombopoiesis. To this end, we used MEG-01 cells, a human megakaryoblastic cell line able to produce in vitro platelet-like particles.2-AG increased the number of cells showing ruffled surface and enhanced surface expression of specific megakaryocyte/platelet surface antigens, typical hallmarks of terminal megakaryocytic differentiation and platelet production. Changes in cytoskeleton modeling also occurred in differentiated megakaryocytes and blebbing platelets. 2-AG acted by binding to CB 1 and CB 2 receptors, because specific antagonists reverted its effect. Platelets were split off from megakaryocytes and were functional: they contained the platelet-specific surface markers CD61 and CD49, whose levels increased following stimulation with a natural agonist like collagen. Given the importance of 2-AG for driving megakaryopoiesis and thrombopoiesis, not surprisingly we found that its hydrolytic enzymes were tightly controlled by classical inducers of megakaryocyte differentiation.In conclusion 2-AG, by triggering megakaryocyte maturation and platelet release, may have clinical efficacy to counteract thrombocytopenia-related diseases.

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Relationships between human vitality and mitochondrial respiratory parameters, reactive oxygen species production and dNTP levels in peripheral blood mononuclear cells

Cited by 32 publications

References 51 publications

The cellular and molecular progression of mitochondrial dysfunction induced by 2,4-dinitrophenol in developing zebrafish embryos

The cellular and molecular progression of mitochondrial dysfunction induced by 2,4-dinitrophenol in developing zebrafish embryos

Prevailing vitamin D status influences mitochondrial and glycolytic bioenergetics in peripheral blood mononuclear cells obtained from adults

2-Arachidonoylglycerol enhances platelet formation from human megakaryoblasts

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