Mitochondrial reactive oxygen species enable proinflammatory signaling through disulfide linkage of NEMO

Herb, Marc; Gluschko, Alexander; Wiegmann, Katja; Farid, Alina; Wolf, Anne; Utermöhlen, Olaf; Krut, Oleg; Krönke, Martin; Schramm, Michael

doi:10.1126/scisignal.aar5926

Cited by 79 publications

(104 citation statements)

References 52 publications

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“…LPS stimulation for 6 hours revealed oxidation of IMS-roGFP, but not matrix-roGFP or cyto-roGFP, the latter of which showed a shift to a reduced state ( Fig.6C , right). This demonstrates the ability of the roGFPs to monitor compartment-specific redox changes in LPS-stimulated macrophages, and supports the hypothesis that LPS-induced mtROS is primarily produced by Complex III into the IMS 12, 86, 87 . In agreement with our MitoPY1 data, pretreatment with hydroxyestrogens, but not their precursor or methylated metabolites, significantly reduced IMS-roGFP oxidation by LPS ( Fig.6D ).…”

Section: Resultssupporting

confidence: 78%

“…reduced inflammation). This concept of a mitochondria-targeted, pro-oxidant therapy to repress inflammation via triggering mitohormetic metabolic reprogramming stands in direct opposition to the concept of using mitochondria-targeted anti-oxidants as anti-inflammatories, which has been employed by others in the macrophage immunometabolism field 12, 75, 86, 87…”

Section: Discussionmentioning

confidence: 99%

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Mitohormesis reprograms macrophage metabolism to enforce tolerance

Timblin

Tharp

Ford

et al. 2020

Preprint

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Macrophages generate mitochondrial reactive oxygen and electrophilic species (mtROS, mtRES) as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here we demonstrate that both pharmacologically- and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state where stimulus-induced proinflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, pharmacologically-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and proinflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mtROS and mtRES are TLR-dependent signaling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signaling and pharmacologically triggering mitohormesis represents a novel anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of proinflammatory gene transcription by mitochondria.

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Section: Resultssupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Mitohormesis reprograms macrophage metabolism to enforce tolerance

Timblin

Tharp

Ford

et al. 2020

Preprint

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“…Mitochondrial ROS can contribute to the activation of NF-κB via several mechanisms: by maintaining phosphorylation of the inhibitor of nuclear factor kappa B (IκB), which prevents nuclear translocation of NF-κB (81,84), and by inhibiting of the activity of NF-κB essential modulator (NEMO), a component of the IκB kinase (IKK) complex that is necessary for NF-κB activation (85).…”

Section: Mitochondrial Rosmentioning

confidence: 99%

The Role Played by Mitochondria in FcεRI-Dependent Mast Cell Activation

et al. 2020

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Mast cells play a key role in the regulation of innate and adaptive immunity and are involved in pathogenesis of many inflammatory and allergic diseases. The most studied mechanism of mast cell activation is mediated by the interaction of antigens with immunoglobulin E (IgE) and a subsequent binding with the high-affinity receptor Fc epsilon RI (FcεRI). Increasing evidences indicated that mitochondria are actively involved in the FcεRI-dependent activation of this type of cells. Here, we discuss changes in energy metabolism and mitochondrial dynamics during IgE-antigen stimulation of mast cells. We reviewed the recent data with regards to the role played by mitochondrial membrane potential, mitochondrial calcium ions (Ca 2+) influx and reactive oxygen species (ROS) in mast cell FcεRI-dependent activation. Additionally, in the present review we have discussed the crucial role played by the pyruvate dehydrogenase (PDH) complex, transcription factors signal transducer and activator of transcription 3 (STAT3) and microphthalmia-associated transcription factor (MITF) in the development and function of mast cells. These two transcription factors besides their nuclear localization were also found to translocate in to the mitochondria and functions as direct modulators of mitochondrial activity. Studying the role played by mast cell mitochondria following their activation is essential for expanding our basic knowledge about mast cell physiological functions and would help to design mitochondria-targeted anti-allergic and anti-inflammatory drugs.

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“…Mitochondrial ROS (MtROS) function on the proinflammatory signaling pathways trigger the production of cytokines. The key pathways causing cytokine production are the MAPK pathways ERK1/2, JNK1/2, and p38 and the pathways leading to NF- κ B activation [ 88 ]. The MtROS can also induce proinflammatory cytokine production in an inflammasome-independent manner, likely by inactivating MAPK phosphatase which adversely regulates the transcription of the proinflammatory cytokine gene [ 89 ].…”

Section: Roles Of Reactive Oxygen Species In the Immune Systemmentioning

confidence: 99%

The Influence of Reactive Oxygen Species in the Immune System and Pathogenesis of Multiple Sclerosis

Tavassolifar

Vodjgani

Salehi

et al. 2020

Autoimmune Diseases

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Multiple roles have been indicated for reactive oxygen species (ROS) in the immune system in recent years. ROS have been extensively studied due to their ability to damage DNA and other subcellular structures. Noticeably, they have been identified as a pivotal second messenger for T-cell receptor signaling and T-cell activation and participate in antigen cross-presentation and chemotaxis. As an agent with direct toxic effects on cells, ROS lead to the initiation of the autoimmune response. Moreover, ROS levels are regulated by antioxidant systems, which include enzymatic and nonenzymatic antioxidants. Enzymatic antioxidants include superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. Nonenzymatic antioxidants contain vitamins C, A, and E, glutathione, and thioredoxin. Particularly, cellular antioxidant systems have important functions in maintaining the redox system homeostasis. This review will discuss the significant roles of ROS generation and antioxidant systems under normal conditions, in the immune system, and pathogenesis of multiple sclerosis.

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Mitochondrial reactive oxygen species enable proinflammatory signaling through disulfide linkage of NEMO

Cited by 79 publications

References 52 publications

Mitohormesis reprograms macrophage metabolism to enforce tolerance

Mitohormesis reprograms macrophage metabolism to enforce tolerance

The Role Played by Mitochondria in FcεRI-Dependent Mast Cell Activation

The Influence of Reactive Oxygen Species in the Immune System and Pathogenesis of Multiple Sclerosis

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