T cell Activation Is Driven by an ADP-Dependent Glucokinase Linking Enhanced Glycolysis with Mitochondrial Reactive Oxygen Species Generation

Kamiński, Marcin M.; Sauer, Sven W.; Kamiński, Marian; Opp, Silvana; Ruppert, Thorsten; Grigaravičius, Paulius; Grudnik, P.; Gröne, Hermann Josef; Krammer, Peter H.; Gülow, Karsten

doi:10.1016/j.celrep.2012.10.009

Cited by 170 publications

(196 citation statements)

References 66 publications

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“…We and others have shown that rotenone, an inhibitor of complex I, blocks T-cell activation-induced ROS generation (Kaminski et al 2007;2010, 2012bYi et al 2006) and, consequently, IL-2, IL-4 and CD95L gene expression (Bauer et al 1998;Kaminski et al 2007Kaminski et al , 2010. Since rotenone interferes with centrosomal function and tubulin assembly (Brinkley et al 1974;Diaz-Corrales et al 2005;Marshall and Himes 1978;Ren et al 2005;), specificity of observed effects was confirmed by additional complex I inhibitors, piericidin A and metformin (an anti-diabetic and mild complex I blocker) (El-Mir et al 2000;Horgan et al 1968;Owen et al 2000).…”

Section: The Enzymatic Sources Of the Oxidative Signalmentioning

confidence: 99%

“…Thus, intact, functional respiratory complex I is indispensible for the oxidative signal generation. Importantly, PMA(DAG)-induced oxidative signal followed the TCR-induced one regarding responsiveness towards mtDNA depletion, all respiratory chain inhibitors tested and NDUFAF1 knock-down (Kaminski et al 2007(Kaminski et al , 2010(Kaminski et al , 2012b.…”

Section: The Enzymatic Sources Of the Oxidative Signalmentioning

confidence: 99%

“…The oxidative signal could not be induced by exclusive Iono (10 lM)-treatment of Jurkat T cells (Gulow et al 2005;Kwon et al 2010), while expanded human T cells were perfectly capable of TCR-induced oxidative signal generation under the Ca 2? -free conditions (phosphate buffered saline) (Kaminski et al 2012b).…”

Section: The Enzymatic Sources Of the Oxidative Signalmentioning

confidence: 99%

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Mitochondria as Oxidative Signaling Organelles in T-cell Activation: Physiological Role and Pathological Implications

Kamiński

Röth

Krammer

et al. 2013

Arch. Immunol. Ther. Exp.

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Section: The Enzymatic Sources Of the Oxidative Signalmentioning

confidence: 99%

Section: The Enzymatic Sources Of the Oxidative Signalmentioning

confidence: 99%

Section: The Enzymatic Sources Of the Oxidative Signalmentioning

confidence: 99%

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Mitochondria as Oxidative Signaling Organelles in T-cell Activation: Physiological Role and Pathological Implications

Kamiński

Röth

Krammer

et al. 2013

Arch. Immunol. Ther. Exp.

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“…Mitochondrial superoxide was also shown to regulate mitochondrial glycerol-3-phosphate dehydrogenase in T-cells. This metabolic shift results in increased glycolysis and increased reduction of mitochondrial respiratory chain (7). Described metabolic changes facilitate T-cell proliferation and cytokine production in models of other disease conditions; however, specific role of mitochondrial superoxide in the immune cells-mediated hypertension is not defined.…”

Section: R99 Mitochondrial Ros In the Prohypertensive Immune Responsementioning

confidence: 99%

Mitochondrial ROS in the prohypertensive immune response

Nazarewicz

Dikalov

2013

American Journal of Physiology-Regulatory, Integrative and Comp

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In the past decade, it has become clear that reactive oxygen species (ROS) and inflammation play an important role in the development of hypertension. Scavenging of mitochondrial superoxide and blocking either IL-17 or tumor necrosis factor-␣ (TNF-␣) attenuates hypertension. T-cells, critical for development of hypertension, once activated intensively produce cytokines, proliferate, and differentiate. Thus T-cell activation leads to expanded energy demand. To fulfill these needs, T-cells through tightly regulated mechanisms, supported by mitochondrial ROS (mtROS), alter their metabolic phenotype. In this review we summarize data and show evidence supporting new concept that mtROS directly contributes to prohypertensive response of immune cells.hypertension; mitochondrial ROS; T cells; immune cell activation; superoxide HYPERTENSION is a multifactorial pathological condition that includes genetic, environmental, neural, endocrine, and humoral causes. In the past decade it has become clear that reactive oxygen species (ROS) and the immune system contribute to all of these factors (4). Phagocytic NADPH oxidase (Nox2) and mitochondria are two key ROS sources in immune cells. Nox2 plays an important role in immune cell regulation, and blocking its expression or its activity reduces cytokine production and cell proliferation. Mitochondria contribute to Nox2 activation (2), regulation of cellular glycolysis, and antigen-specific expansion of T-cells (9). The underlining precise mechanisms, however, are not clear.T-cells are critical for hypertension (5); however, the exact mechanism of T-cell activation in hypertension has not been fully understand. Once activated, T-cells intensively proliferate, produce cytokines that further stimulate immune system, alter vascular function, and stimulate ROS production. Mitochondrial ROS (mtROS) regulates cellular signaling, cell functions, and metabolism. It controls major mitochondrial and cytoplasmic metabolic pathways, such as glycolysis and the citric acid cycle (Krebs cycle). Rapidly proliferating cells, including immune cells, may rely on glycolysis to fulfill growing energy needs. To trigger changes in metabolism, cells increase ROS and through tightly regulated mechanisms alter metabolic phenotype. Cellular sources of ROS are also required for immune cell activation and their responses. Knocking down in T-cells p47 phox, a NOX2 subunit, prevents tumor necrosis factor-␣ (TNF-␣) production, a cytokine that is critical for the development of hypertension (5). Inhibition of TNF-␣ mutes hypertension; thus, scavenging ROS in immune cells may attenuate their prohypertensive responses. Targeting ROS-sensitive signaling pathways could be a new strategy to treat hypertension. In fact, overexpression of mitochondrial SOD in mice prevents development of hypertension, or treatment mice with low doses of mitochondria-targeted SOD mimetic reverses fully developed hypertension (3). We and others (3, 12) have found that angiotensin II-induced hypertension leads to endothelial dysfunction de...

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“…Oxidative signals can be regulated by the TCRtriggered activation of ADP-dependent glucokinase (ADPGK), which increases glycolytic metabolism and diverts glycolysis toward the mitochondrial glycerol-3-phosphate dehydrogenase (GPD) shuttle. The activation of GPD2 results in hyperreduction of ubiquinone and release of ROS from mitochondria, resulting in the upregulation of NF-κB-dependent gene expression [93]. Mitochondrial ROS signaling is thus required for antigen-specific T cell activation, highlighting the critical importance of mitochondrial metabolism in the regulation of the T cell nuclear program.…”

Section: Mitochondria Ros and Nuclear Activationmentioning

confidence: 99%

Immune synapse: conductor of orchestrated organelle movement

Martín-Cófreces¹,

Baixauli²,

Sánchez-Madrid³

2014

Trends in Cell Biology

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SummaryTo ensure proper cell function, intracellular organelles are not randomly distributed within the cell, but polarized and highly constrained by the cytoskeleton and associated adaptor proteins. This relationship between distribution and function was originally found in neurons and epithelial cells; however, recent evidence suggests that it is a more general phenomenon that occurs in many highly specialized cells including the immune T cells. Recent studies reveal that the orchestrated redistribution of organelles is dependent on antigen specific activation and immune-synapse formation of T cells. This review highlights the functional implications of organelle polarization in early T cell activation and examines recent findings on how the immune synapse sets the rhythm of organelle motion and the spread of the activation signal to the nucleus. KeywordsImmune synapse; microcluster; signalosome; mitochondria; vesicle; microtubule Overview of the immune synapseT cell activation starts with an initial wave of signalling that depends on the activation of surface receptors, but subsequent propagation of the signal appears to depend on intracellular compartments, in a sequence driven by the actin and tubulin cytoskeletons [1]. The study of neural synapses highlighted the importance of cell polarity and the specific localization of organelles and clusters of receptors at the pre-and post-synaptic terminals. Despite its transient nature, recent evidence shows that the immune synapse (IS) shares these same neuronal features.The IS is the interface between a T lymphocyte and an antigen presenting cell (APC). During the formation and stabilization of the IS, membrane microdomains and the cytoskeleton reorganize and promote the segregation of membrane and intracellular signaling proteins within the T cell, such as the T cell receptor (TCR), integrins, tyrosine Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts kinases and scaffold proteins such as Linker for activation of T cells (LAT) (Figure 1 and Glossary). The TCR and associated molecules (TCR signalosomes) form microclusters that move to congregate in the central area (central supramolecular activation cluster; cSMAC) of the IS, whereas adhesion receptors such as integrins reorganize in a surrounding external ring called the peripheral or pSMAC ( Figure 2) [2]. In addition, phosphorylation and dephosphorylation, protein-protein interactions and degradation of important molecules such as the TCR-accompanying CD3 complex, tyrosine kinases, phosphatases and adaptor molecules also control receptor activation [3,4]. The polarization of several organelles occurs during T cell stimulation with important roles, such as the centrosome, Golgi apparatus, mitochondria, endoplasmic reticulum and the multivesicular bodies (MVB) [5][6][7][8][9][10]. These rearrangements at the IS promote the activation of signaling pathways that propagate to the nucleus. Signals activating nuclear transcription factors in combination with polarity proteins, such as partit...

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T cell Activation Is Driven by an ADP-Dependent Glucokinase Linking Enhanced Glycolysis with Mitochondrial Reactive Oxygen Species Generation

Cited by 170 publications

References 66 publications

Mitochondria as Oxidative Signaling Organelles in T-cell Activation: Physiological Role and Pathological Implications

Mitochondria as Oxidative Signaling Organelles in T-cell Activation: Physiological Role and Pathological Implications

Mitochondrial ROS in the prohypertensive immune response

Immune synapse: conductor of orchestrated organelle movement

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