Mitochondrial redox signalling at a glance

Collins, Yvonne; Chouchani, Edward T.; James, Andrew M.; Menger, Katja E.; Cochemé, Helena M.; Murphy, Michael P.

doi:10.1242/jcs.098475

Cited by 230 publications

(155 citation statements)

References 118 publications

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“…These findings are in line with the prevailing view that ROS act as biological messengers principally through reversible modification of sensitive surface cysteine residues on proteins (7,12). Recently developed methodologies now allow for the identification and quantification of redox-modified protein cysteine residues in intact cells and living tissue (44 -46).…”

Section: Molecular Targets Of Thermogenic Rossupporting

confidence: 78%

Mitochondrial reactive oxygen species and adipose tissue thermogenesis: Bridging physiology and mechanisms

Chouchani

Kazak

Spiegelman

2017

Journal of Biological Chemistry

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Edited by Ruma BanerjeeBrown and beige adipose tissues can catabolize stored energy to generate heat, relying on the principal effector of thermogenesis: uncoupling protein 1 (UCP1). This unique capability could be leveraged as a therapy for metabolic disease. Numerous animal and cellular models have now demonstrated that mitochondrial reactive oxygen species (ROS) signal to support adipocyte thermogenic identity and function. Herein, we contextualize these findings within the established principles of redox signaling and mechanistic studies of UCP1 function. We provide a framework for understanding the role of mitochondrial ROS signaling in thermogenesis together with testable hypotheses for understanding mechanisms and developing therapies. Brown adipose tissue (BAT)2 has long been recognized as a critical thermogenic organ, exemplified by its importance in maintenance of thermal homeostasis in cold environments (1). More recently, clusters of distinct adipocytes with thermogenic capacity have been characterized in white adipose tissue-beige adipocytes-arising in response to various physiological stimuli (2, 3). The thermogenic endowment of these tissues has prompted the reasonable hypothesis that they might be leveraged to catabolize lipid and glucose as an anti-obesity and antidiabetic therapy. As such, recent decades have seen vigorous research into the mechanisms controlling brown and beige adipose tissue identity and function. Thermogenesis in BAT and beige adipose tissue relies on the key effector protein uncoupling protein 1 (UCP1), which can dissipate the electrochemical H ϩ gradient across the inner mitochondrial membrane (4). This UCP1-mediated inducible proton "leak" uncouples protonmotive force from ATP synthesis leading to an increased rate of mitochondrial respiration and heat generation. Additionally, UCP1-independent effectors of thermogenesis have been uncovered in recent years, including utilization of creatine-dependent substrate cycling in beige adipose tissue (5). Of course, expression of UCP1 (or other effectors) per se is not sufficient to drive thermogenesis; these are gas pedals that need a foot, fuel, and an engine. Indeed, thermogenic adipocytes require exceptionally high mitochondrial content and oxidative capacity to support elevated respiration. Moreover, thermogenic respiration is regulated acutely by upstream physiological signals that are required to activate UCP1-mediated uncoupling. So, elucidating the mechanisms that activate thermogenically-poised adipocytes is critical from a therapeutic standpoint.The purpose of this review is to contextualize recent findings that provide evidence for an important signaling role by reactive oxygen species (ROS) in adipose tissue thermogenesis. Remarkably, the importance of ROS signaling in this context has been demonstrated primarily through investigation of redox metabolism using in vivo mouse and intact adipocyte models of thermogenesis. In contrast, studies of ROS and thermogenesis using in vitro and reconstituted systems have provided...

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Section: Molecular Targets Of Thermogenic Rossupporting

confidence: 78%

Mitochondrial reactive oxygen species and adipose tissue thermogenesis: Bridging physiology and mechanisms

Chouchani

Kazak

Spiegelman

2017

Journal of Biological Chemistry

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“…As pointed out earlier, Ca 2+ influx accelerates the generation of mROS (30). Furthermore, triggering of certain TLRs in immune cells results in formation of mROS important for bactericidal activity and for regulation of redox-sensitive signaling pathways regulating cytokine release and Ag-presenting capacity (22,26). It has been shown that ROS production in DCs upon communication with cocultured T cells determines their Ag-presentation capacity (46,47).…”

Section: Discussionmentioning

confidence: 91%

“…Especially their role in immune cell signaling has gained much attention in recent years (24,25). Apart from regulating apoptosis, mitochondrial release of ROS is instrumental for redoxsensitive signaling pathways such as activation of MAP kinases, NF-kB, and AP1 as well as mitochondria are indispensable for Ca 2+ signaling (22,(26)(27)(28)(29). Mitochondria are efficient Ca 2+ buffers (30).…”

Section: Discussionmentioning

confidence: 99%

TCAIM Decreases T Cell Priming Capacity of Dendritic Cells by Inhibiting TLR-Induced Ca2+ Influx and IL-2 Production

Vogel

Schlickeiser

Jürchott

et al. 2015

The Journal of Immunology

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We previously showed that the T cell activation inhibitor, mitochondrial (Tcaim) is highly expressed in grafts of tolerance-developing transplant recipients and that the encoded protein is localized within mitochondria. In this study, we show that CD11c+ dendritic cells (DCs), as main producers of TCAIM, downregulate Tcaim expression after LPS stimulation or in vivo alloantigen challenge. LPS-stimulated TCAIM-overexpressing bone marrow–derived DC (BMDCs) have a reduced capacity to induce proliferation of and cytokine expression by cocultured allogeneic T cells; this is not due to diminished upregulation of MHC or costimulatory molecules. Transcriptional profiling also revealed normal LPS-mediated upregulation of the majority of genes involved in TLR signaling. However, TCAIM BMDCs did not induce Il2 mRNA expression upon LPS stimulation in comparison with Control-BMDCs. In addition, TCAIM overexpression abolished LPS-mediated Ca2+ influx and mitochondrial reactive oxygen species formation. Addition of IL-2 to BMDC–T cell cocultures restored the priming capacity of TCAIM BMDCs for cocultured allogeneic CD8+ T cells. Furthermore, BMDCs of IL-2–deficient mice showed similarly abolished LPS-induced T cell priming as TCAIM-overexpressing wild type BMDCs. Thus, TCAIM interferes with TLR4 signaling in BMDCs and subsequently impairs their T cell priming capacity, which supports its role for tolerance induction.

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“…Currently, it is widely accepted that redox signals to and from mitochondria are at the core of a wide variety of biological processes, including cell proliferation and differentiation, adaptation to hypoxia, autophagy, immune function, and hormone signaling (Figure 2) (Collins et al, 2012;Chandel, 2014). The most studied and best characterized mitochondrial redox signaling molecule is H 2 O 2 , which is relatively stable in vivo and can pass easily through mitochondrial membranes (Bienert et al, 2006).…”

Section: Mitochondria As Redox Signaling Nodesmentioning

confidence: 99%

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

2017

Frontiers Research Topics

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Mitochondrial redox signalling at a glance

Cited by 230 publications

References 118 publications

Mitochondrial reactive oxygen species and adipose tissue thermogenesis: Bridging physiology and mechanisms

Mitochondrial reactive oxygen species and adipose tissue thermogenesis: Bridging physiology and mechanisms

TCAIM Decreases T Cell Priming Capacity of Dendritic Cells by Inhibiting TLR-Induced Ca2+ Influx and IL-2 Production

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

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