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      A review of the mitochondrial and glycolytic metabolism in human platelets and leukocytes: Implications for their use as bioenergetic biomarkers

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          Abstract

          The assessment of metabolic function in cells isolated from human blood for treatment and diagnosis of disease is a new and important area of translational research. It is now becoming clear that a broad range of pathologies which present clinically with symptoms predominantly in one organ, such as the brain or kidney, also modulate mitochondrial energetics in platelets and leukocytes allowing these cells to serve as “the canary in the coal mine” for bioenergetic dysfunction. This opens up the possibility that circulating platelets and leukocytes can sense metabolic stress in patients and serve as biomarkers of mitochondrial dysfunction in human pathologies such as diabetes, neurodegeneration and cardiovascular disease. In this overview we will describe how the utilization of glycolysis and oxidative phosphorylation differs in platelets and leukocytes and discuss how they can be used in patient populations. Since it is clear that the metabolic programs between leukocytes and platelets are fundamentally distinct the measurement of mitochondrial function in distinct cell populations is necessary for translational research.

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          Highlights

          • Monocytes, lymphocytes, neutrophils and platelets have distinct bioenergetic programs that regulate energy production.

          • Platelets and monocytes exhibit a high level of aerobic glycolysis and mitochondrial respiration.

          • Lymphocytes have a low glycolytic capacity while neutrophils have little or no detectable oxidative phosphorylation.

          • The levels of mitochondrial complex IV and III subunits differ substantially between lymphocytes, monocytes and platelets.

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          Most cited references25

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          Fueling immunity: insights into metabolism and lymphocyte function.

          Lymphocytes face major metabolic challenges upon activation. They must meet the bioenergetic and biosynthetic demands of increased cell proliferation and also adapt to changing environmental conditions, in which nutrients and oxygen may be limiting. An emerging theme in immunology is that metabolic reprogramming and lymphocyte activation are intricately linked. However, why T cells adopt specific metabolic programs and the impact that these programs have on T cell function and, ultimately, immunological outcome remain unclear. Research on tumor cell metabolism has provided valuable insight into metabolic pathways important for cell proliferation and the influence of metabolites themselves on signal transduction and epigenetic programming. In this Review, we highlight emerging concepts regarding metabolic reprogramming in proliferating cells and discuss their potential impact on T cell fate and function.
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            Requirements for NADPH oxidase and myeloperoxidase in neutrophil extracellular trap formation differ depending on the stimulus.

            Release of NETs by neutrophils is linked with immune protection and host damage. A variety of stimuli promotes NET formation. However, findings from different laboratories often vary, and it is possible that more than one mechanism of NET formation exists. NET formation induced by PMA has been shown to require NADPH oxidase activity, and there is evidence that the granule enzyme MPO is also involved. However, requirements for NADPH oxidase or MPO with other stimuli are less well established. We investigated the role of oxidants in NET formation by human neutrophils induced with PMA, several bacterial genera, and the calcium ionophore ionomycin. With the use of inhibitors of the NADPH oxidase and MPO, oxidant scavengers, and cells from a MPO-deficient individual, we observed that requirements for oxidant generation depend on the stimulus. NADPH oxidase activity was required with PMA and bacterial stimulation but not with ionomycin. Whereas MPO was required for efficient NET formation with PMA, incubation with bacteria induced NETs independently of MPO activity. Although the specific mechanisms whereby oxidants participate in NET formation remain to be clarified, it is possible that other stimuli that mobilize calcium act like ionomycin via an oxidant-independent mechanism, and it cannot be inferred from results with PMA that MPO is required with more physiological stimuli.
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              Transcriptional control of macrophage polarization.

              Macrophages are key regulators of many organ systems, including innate and adaptive immunity, systemic metabolism, hematopoiesis, vasculogenesis, malignancy, and reproduction. The pleiotropic roles of macrophages are mirrored by similarly diverse cellular phenotypes. A simplified schema classifies macrophages as M1, classically activated macrophages, or M2, alternatively activated macrophages. These cells are characterized by their expression of cell surface markers, secreted cytokines and chemokines, and transcription and epigenetic pathways. Transcriptional regulation is central to the differential speciation of macrophages, and several major pathways have been described as essential for subset differentiation. In this review, we discuss the transcriptional regulation of macrophages.
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                Author and article information

                Journal
                Redox Biol
                Redox Biol
                Redox Biology
                Elsevier
                2213-2317
                10 January 2014
                10 January 2014
                2014
                : 2
                : 206-210
                Affiliations
                [0005]Department of Pathology, UAB Mitochondrial Medicine Laboratory, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
                Author notes
                [* ]Correspondence to: Department of Pathology, University of Alabama at Birmingham, Biomedical Research Building II, 901 19th Street, South Birmingham, AL 35294, USA. Tel.: +1 205 975 9686; fax: +1 205 934 1775. Darley@ 123456uab.edu
                [1]

                These authors contributed equally to this work.

                Article
                S2213-2317(14)00009-3
                10.1016/j.redox.2013.12.026
                3909784
                24494194
                61e3c5cf-195c-4cc3-ae3c-3a763c8e8eae
                © 2014 The Authors
                History
                : 30 December 2013
                : 30 December 2013
                Categories
                Mini Review

                xf, extracellular flux analyzer,metabolic shift,leukocytes,ros/rns, reactive oxygen species/reactive nitrogen species,ecar, extracellular acidification rate,biomarker,oxidative stress,platelets,reserve capacity,ocr, oxygen consumption rate

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