Fus1/Tusc2 Is a Novel Regulator of Mitochondrial Calcium Handling, Ca2+-Coupled Mitochondrial Processes, and Ca2+-Dependent NFAT and NF-κB Pathways in CD4+T Cells

Uzhachenko, Roman V.; Ivanov, Sergey V.; Yarbrough, Wendell G.; Shanker, Anil; Medzhitov, Ruslan; Ivanova, Alla V.

doi:10.1089/ars.2013.5437

Cited by 35 publications

(109 citation statements)

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“…Ϫ/Ϫ CD4 ϩ T cells, activation of the NF-B pathway is prominent at a basal level that we associated with a perturbed mitochondrial Ca 2ϩ homeostasis and other coupled mitochondrial parameters in these cells (30).…”

Section: Discussionmentioning

confidence: 62%

“…Calprotectin plays an important role in defense against A. baumannii infection through chelation of nutrient Mn and Zn (19). We also showed recently that expression of S100A8 and S100A9, the components of calprotectin complex, is 3-fold higher in Fus1 Ϫ/Ϫ T cells than in Fus1 ϩ/ϩ cells (30). Interestingly, while other groups have shown that in WT C57BL/6 mice IL-17 does not play a significant role in defense against A. baumannii infection, we have shown significant upregulation of IL-17 in Fus1 Ϫ/Ϫ mice after A. baumannii intranasal challenge.…”

Section: Discussionmentioning

confidence: 79%

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Loss of Mitochondrial Protein Fus1 Augments Host Resistance to Acinetobacter baumannii Infection

et al. 2013

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cFus1 is a tumor suppressor protein with recently described immunoregulatory functions. Although its role in sterile inflammation is being elucidated, its role in regulating immune responses to infectious agents has not been examined. We used here a murine model of Acinetobacter baumannii pneumonia to identify the role of Fus1 in antibacterial host defenses. We found that the loss of Fus1 in mice results in significantly increased resistance to A. baumannii pneumonia. We observed earlier and more robust recruitment of neutrophils and macrophages to the lungs of infected Fus1 ؊/؊ mice, with a concomitant increase in phagocytosis of invading bacteria and more rapid clearance. Such a prompt and enhanced immune response to bacterial infection in Fus1 ؊/؊ mice stems from early activation of proinflammatory pathways (NF-B and phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin [mTOR]), most likely due to significantly increased mitochondrial membrane potential and mitochondrial reactive oxygen species production. Significant early upregulation of interleukin-17 (IL-17) in Fus1 ؊/؊ immune cells was also observed, together with significant downregulation of IL-10. Depletion of neutrophils eliminates the enhanced antibacterial defenses of the Fus1 ؊/؊ mice, suggesting that ultimately it is the enhanced immune cell recruitment that mediates the increased resistance of Fus1 ؊/؊ mice to A. baumannii pneumonia. Taken together, our data define the novel role for Fus1 in the immune response to A. baumannii pneumonia and highlight new avenues for immune modulating therapeutic targets for this treatment-resistant nosocomial pathogen.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 79%

Loss of Mitochondrial Protein Fus1 Augments Host Resistance to Acinetobacter baumannii Infection

et al. 2013

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“…Aging is itself related to the production of free radicals and it has been proposed that excess of free radicals may contribute to amyloid beta aggregation (Christen, 2000). In the present work, we introduce the Fus1 KO mouse as a novel model for sAD that combines premature aging, chronic oxidative stress due to high ROS production and inadequate anti-oxidant machinery, mitochondrial dysfunction, low grade chronic inflammation and aberrant acute inflammatory response (Ivanova et al, 2007; Uzhachenko et al, 2012, 2014; Hood et al, 2013). This model is highly relevant to sAD as increased ROS generation and oxidative damage occur early in the progress of sAD.…”

Section: Discussionmentioning

confidence: 99%

“…Fus1 is involved in regulation of inflammatory and stress responses to various stimuli, infection agents and tumor growth (Hood et al, 2013; Yazlovitskaya et al, 2013, 2015). Fus1 deficient mice display signs of chronic inflammation including increased cytokine production, NF-κB activation and increased levels of ROS (Uzhachenko et al, 2012, 2014). Inflammation leading to ROS production, one of the causative factors of aging, has been shown to reduce expression of Fus1.…”

Section: Introductionmentioning

confidence: 99%

Fus1 KO Mouse As a Model of Oxidative Stress-Mediated Sporadic Alzheimer's Disease: Circadian Disruption and Long-Term Spatial and Olfactory Memory Impairments

Coronas‐Samano

Baker

Tan

et al. 2016

Front. Aging Neurosci.

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Insufficient advances in the development of effective therapeutic treatments of sporadic Alzheimer's Disease (sAD) to date are largely due to the lack of sAD-relevant animal models. While the vast majority of models do recapitulate AD's hallmarks of plaques and tangles by virtue of tau and/or beta amyloid overexpression, these models do not reflect the fact that in sAD (unlike familial AD) these genes are not risk factors per se and that other mechanisms like oxidative stress, metabolic dysregulation and inflammation play key roles in AD etiology. Here we characterize and propose the Fus1 KO mice that lack a mitochondrial protein Fus1/Tusc2 as a new sAD model. To establish sAD relevance, we assessed sAD related deficits in Fus1 KO and WT adult mice of 4–5 months old, the equivalent human age when the earliest cognitive and olfactory sAD symptoms arise. Fus1 KO mice showed oxidative stress (increased levels of ROS, decreased levels of PRDX1), disruption of metabolic homeostasis (decreased levels of ACC2, increased phosphorylation of AMPK), autophagy (decreased levels of LC3-II), PKC (decreased levels of RACK1) and calcium signaling (decreased levels of Calb2) in the olfactory bulb and/or hippocampus. Mice were behaviorally tested using objective and accurate video tracking (Noldus), in which Fus1 KO mice showed clear deficits in olfactory memory (decreased habituation/cross-habituation in the short and long term), olfactory guided navigation memory (inability to reduce their latency to find the hidden cookie), spatial memory (learning impairments on finding the platform in the Morris water maze) and showed more sleep time during the diurnal cycle. Fus1 KO mice did not show clear deficits in olfactory perception (cross-habituation), association memory (passive avoidance) or in species-typical behavior (nest building) and no increased anxiety (open field, light-dark box) or depression/anhedonia (sucrose preference) at this relatively young age. These neurobehavioral deficits of the Fus1 KO mice at this relatively young age are highly relevant to sAD, making them suitable for effective research on pharmacological targets in the context of early intervention of sAD.

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“…The loss of Fus1 results in an autoimmune-like syndrome with chronic inflammation and the spontaneous formation of both vascular tumors and lymphomas. Recent studies have shown that Fus-1 plays important roles in carcinogenesis [29]. The Fus-1 3′ UTR includes a potential target sequence of miR-378 in nucleotides 748-770.…”

Section: Introductionmentioning

confidence: 99%

MiR-378 Promotes the Migration of Liver Cancer Cells by Down-Regulating Fus Expression

Jiang

Qian

et al. 2014

Cell Physiol Biochem

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Background: miR-378 regulates osteoblast differentiation and participates in tumor cell self-renewal and chemo-resistance. However, the function of miR-378 in liver cancer cell migration has not been reported to date. Methods: miR-378 expression was examined using real-time quantitative PCR. HepG2 cell migration and liver cell invasion were examined using wound-healing and cell invasion assays. Additionally, HepG2 cell metastasis was analyzed in nude mice. Results: miR-378 over-expression enhances HepG2 cell proliferation, migration and liver cell invasion. Typical metastatic lesions were found in the livers of mice injected with miR-378-transfected cells, and high levels of the CMV promoter were detected in the nodules, indicating that miR-378 promoted the metastasis of the tumor cells to the liver. We also demonstrated that miR-378 down-regulated Fus expression. Conclusions: Our results suggested that miR-378 enhanced cell migration and metastasis by down-regulating Fus expression.

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Fus1/Tusc2 Is a Novel Regulator of Mitochondrial Calcium Handling, Ca²⁺-Coupled Mitochondrial Processes, and Ca²⁺-Dependent NFAT and NF-κB Pathways in CD4⁺T Cells

Abstract: Our findings suggest that Fus1 achieves its protective role in inflammation, autoimmunity, and cancer via the regulation of mitochondrial calcium and calcium-coupled parameters.

Cited by 35 publications

References 70 publications

Loss of Mitochondrial Protein Fus1 Augments Host Resistance to Acinetobacter baumannii Infection

Loss of Mitochondrial Protein Fus1 Augments Host Resistance to Acinetobacter baumannii Infection

Fus1 KO Mouse As a Model of Oxidative Stress-Mediated Sporadic Alzheimer's Disease: Circadian Disruption and Long-Term Spatial and Olfactory Memory Impairments

MiR-378 Promotes the Migration of Liver Cancer Cells by Down-Regulating Fus Expression

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