A Mitochondria-Targeted Triphenylphosphonium-Conjugated Nitroxide Functions as a Radioprotector/Mitigator

Jiang, Jianing; Stoyanovsky, Detcho A.; Belikova, Natalia A.; Tyurina, Yulia Y.; Zhao, Qing; Tungekar, Muhammad A.; Kapralova, Valentyna I.; Huang, Zhentai; Mintz, Arlan; Greenberger, Joel S.; Kagan, Valerian E.

doi:10.1667/rr1729.1

Cited by 70 publications

(69 citation statements)

References 37 publications

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“…4A, data not shown). To examine whether the inhibitory effect of CO on mitochondrial ROS generation was associated with the effect of CO on the NLRP3 inflammasome, we scavenged mitochondrial ROS by Mito-TEMPO, a derivative of the antioxidant TEMPO that concentrates in the mitochondrial matrix and acts as an O 2 Ϫ scavenger (22,58). Consistent with our previous reports, Mito-TEMPO treatment significantly inhibited IL-18 secretion in BMDMs stimulated with LPS and ATP (Fig.…”

Section: Co Inhibits Caspase-1 Activation By Regulating the Nlrp3 Infsupporting

confidence: 82%

Carbon monoxide negatively regulates NLRP3 inflammasome activation in macrophages

Jung

Moon

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Inflammasomes are cytosolic protein complexes that promote the cleavage of caspase-1, which leads to the maturation and secretion of proinflammatory cytokines, including interleukin-1β (IL-1β) and IL-18. Among the known inflammasomes, the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3)-dependent inflammasome is critically involved in the pathogenesis of various acute or chronic inflammatory diseases. Carbon monoxide (CO), a gaseous molecule physiologically produced in cells and tissues during heme catabolism, can act as an anti-inflammatory molecule and a potent negative regulator of Toll-like receptor signaling pathways. To date, the role of CO in inflammasome-mediated immune responses has not been fully investigated. Here, we demonstrated that CO inhibited caspase-1 activation and the secretion of IL-1β and IL-18 in response to lipopolysaccharide (LPS) and ATP treatment in bone marrow-derived macrophages. CO also inhibited IL-18 secretion in response to LPS and nigericin treatment, another NLRP3 inflammasome activation model. In contrast, CO did not suppress IL-18 secretion in response to LPS and poly(dA:dT), an absent in melanoma 2 (AIM2)-mediated inflammasome model. LPS and ATP stimulation induced the formation of complexes between NLRP3 and apoptosis-associated speck-like protein, or NLRP3 and caspase-1. CO treatment inhibited these molecular interactions that were induced by LPS and ATP. Furthermore, CO inhibited mitochondrial ROS generation and the decrease of mitochondrial membrane potential induced by LPS and ATP in macrophages. We also observed that the inhibitory effect of CO on the translocation of mitochondrial DNA into the cytosol was associated with suppression of cytokine secretion. Our results suggest that CO negatively regulates NLRP3 inflammasome activation by preventing mitochondrial dysfunction.

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Section: Co Inhibits Caspase-1 Activation By Regulating the Nlrp3 Infsupporting

confidence: 82%

Carbon monoxide negatively regulates NLRP3 inflammasome activation in macrophages

Jung

Moon

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In this study, we show that scavenging of mitochondrial ROS with Mito-TEMPO, a triphenylphosphonium-conjugated antioxidant that localizes to the mitochondria (38), inhibits the activation of LC3B by CO, indicating a role for mitochondrialderived ROS in the activation of autophagy by CO. Recent literature has identified the preferential mitochondrial localization and ROS scavenging effect of Mito-TEMPO (38,39).…”

Section: Discussionmentioning

confidence: 66%

“…Recent literature has identified the preferential mitochondrial localization and ROS scavenging effect of Mito-TEMPO (38,39). Although mitochondria-derived ROS are thought to arise primarily from respiratory activity, we cannot completely exclude the potential contribution of ROS from other cytosolic sources, such as nonphagocytic NADPH oxidase isoforms, in the signaling effects of CO.…”

Section: Discussionmentioning

confidence: 84%

Carbon Monoxide Activates Autophagy via Mitochondrial Reactive Oxygen Species Formation

Lee

Ryter

et al. 2011

Am J Respir Cell Mol Biol

111

108

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Autophagy, an autodigestive process that degrades cellular organelles and protein, plays an important role in maintaining cellular homeostasis during environmental stress. Carbon monoxide (CO), a toxic gas and candidate therapeutic molecule, confers cytoprotection in animal models of acute lung injury. The mechanisms underlying CO-dependent lung cell protection and the role of autophagy in this process remain unclear. Here, we demonstrate that CO exposure time-dependently increased the expression and activation of the autophagic protein, microtubule-associated protein-1 light chain-3B (LC3B) in mouse lung, and in cultured human alveolar (A549) or human bronchial epithelial cells. Furthermore, CO increased autophagosome formation in epithelial cells by electron microscopy and green fluorescent protein (GFP)-LC3 puncta assays. Recent studies indicate that reactive oxygen species (ROS) play an important role in the activation of autophagy. CO up-regulated mitochondria-dependent generation of ROS in epithelial cells, as assayed by MitoSOX fluorescence. Furthermore, CO-dependent induction of LC3B expression was inhibited by N-acetyl-L-cysteine and the mitochondria-targeting antioxidant, Mito-TEMPO. These data suggest that CO promotes the autophagic process through mitochondrial ROS generation. We investigated the relationships between autophagic proteins and CO-dependent cytoprotection using a model of hyperoxic stress. CO protected against hyperoxia-induced cell death, and inhibited hyperoxia-associated ROS production. The ability of CO to protect against hyperoxia-induced cell death and caspase-3 activation was compromised in epithelial cells infected with LC3B-small interfering (si)RNA, indicating a role for autophagic proteins. These studies uncover a new mechanism for the protective action of CO, in support of potential therapeutic application of this gas.Keywords: apoptosis; autophagy; carbon monoxide; epithelial cells; hyperoxia Carbon monoxide (CO), a low-molecular weight diatomic gas, can induce clinical toxicity and even death at high ambient concentrations (1). The adverse effects of CO in humans are associated with hypoxemia as the result of competitive binding of CO with the heme iron centers of the oxygen carrier protein hemoglobin (2, 3). The cellular toxicity of CO may involve complex formation and inhibition of respiratory chain enzymes (i.e., cytochrome c: oxidase) (4, 5). In contrast to these toxic mechanisms, recent studies over the last decade have revealed cyto-and tissue-protective effects of CO when applied at low ambient concentrations in several models of lung or vascular injury, including acute lung injury (i.e., endotoxin shock, hyperoxia, mechanical ventilation), and ischemia-reperfusion injury (6-12). The protective effects of CO in these models depend on anti-inflammatory, antiapoptotic, and/or antiproliferative activities of this gas (13). Several signaling pathways have been implicated in CO-dependent cytoprotection, including the p38 mitogen activated protein kinase (MAPK) and NF-kB ...

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“…MitoTEMPO has been identified to have a preferential mitochondrial location for its ROS-scavenging effect (39). The fact that autophagic protein-depleted MSCs could be rescued from cell death by MitoTEMPO supports the strong impact that mitochondrial ROS and mitochondrial dysfunction have on the survival of these cells under oxidative stress.…”

Section: Discussionmentioning

confidence: 87%

Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction

Ghanta

Tsoyi

Liu

et al. 2017

Am J Respir Cell Mol Biol

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Oxidative stress resulting from inflammatory responses that occur during acute lung injury and sepsis can initiate changes in mitochondrial function. Autophagy regulates cellular processes in the setting of acute lung injury, sepsis, and oxidative stress by modulating the immune response and facilitating turnover of damaged cellular components. We have shown that mesenchymal stromal cells (MSCs) improve survival in murine models of sepsis by also regulating the immune response. However, the effect of autophagy on MSCs and MSC mitochondrial function during oxidative stress is unknown. This study investigated the effect of depletion of autophagic protein microtubule-associated protein 1 light chain 3B (LC3B) and beclin 1 (BECN1) on the response of MSCs to oxidative stress. MSCs were isolated from wild-type (WT) and LC3B 2/2 or Becn1 1/2 mice. MSCs from the LC3B 2/2 and Becn1 1/2 animals had increased susceptibility to oxidative stress-induced cell death as compared with WT MSCs. The MSCs depleted of autophagic proteins also had impaired mitochondrial function (decreased intracellular ATP, reduced mitochondrial membrane potential, and increased mitochondrial reactive oxygen species production) under oxidative stress as compared with WT MSCs. In WT MSCs, carbon monoxide (CO) preconditioning enhanced autophagy and mitophagy, and rescued the cells from oxidative stress-induced death. CO preconditioning was not able to rescue the decreased survival of MSCs from the LC3B 2/2 and Becn1 1/2 animals, further supporting the tenet that CO exerts its cytoprotective effects via the autophagy pathway.

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A Mitochondria-Targeted Triphenylphosphonium-Conjugated Nitroxide Functions as a Radioprotector/Mitigator

Cited by 70 publications

References 37 publications

Carbon monoxide negatively regulates NLRP3 inflammasome activation in macrophages

Carbon monoxide negatively regulates NLRP3 inflammasome activation in macrophages

Carbon Monoxide Activates Autophagy via Mitochondrial Reactive Oxygen Species Formation

Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction

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