The Mitochondrial Isoform of FASTK Modulates Nonopsonic Phagocytosis of Bacteria by Macrophages via Regulation of Respiratory Complex I

Río, Ana García del; Delmiro, Aitor; Martín, Miguel; Cantalapiedra, Roberto; Carretero, Raquel; Durantez-Fernández, Carlos; Menegotto, Fabíola; Morán, María; Serrano‐Lorenzo, Pablo; Fuente, Miguel A. de la; Orduña, Antonio; Simarro, Marı́a

doi:10.4049/jimmunol.1701075

Cited by 8 publications

(7 citation statements)

References 46 publications

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“…FASTK is recently identified as a RNA-binding protein to promote MTND6 mRNA maturation (Jourdain et al, 2015). Genetic ablation of FASTK causes a marked reduction of complex I activity in mammalian cells, highlighting FASTK is essential to maintain normal complex I function (García Del Río et al, 2018;Gomez-Niño et al, 2018). The present study shows that the FASTK deficient heart is highly susceptible to I/R-induced complex I dysfunction and respiration, confirming that FASTK critically modulates myocardial mitochondrial complex I activity even under stressful conditions such as I/R.…”

Section: Discussionsupporting

confidence: 73%

“…In mammalian cells, FASTK specifically interacts with the mRNA of NADH dehydrogenase subunit 6 (MTND6, a mitochondrial gene encoding a subunit of complex I) at various sites and is essential for the processing and maturation of MTND6 mRNA (Jourdain et al, 2015). In vivo and in vitro studies have confirmed that genetic ablation of FASTK decreased the expression of MTND6 and thereafter suppressed mitochondrial complex I activity approximately by 50% (García Del Río et al, 2018;Gomez-Niño et al, 2018). These data reveal that FASTK is a novel and important modulator of mitochondrial complex I activity and respiratory function.…”

Section: Introductionmentioning

confidence: 99%

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Fas-Activated Serine/Threonine Kinase Governs Cardiac Mitochondrial Complex I Functional Integrity in Ischemia/Reperfusion Heart

Chen

Wang

et al. 2021

Front. Cell Dev. Biol.

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Cardiac energy homeostasis is strictly controlled by the mitochondrial complex-mediated respiration. In the heart, mitochondrial complex I is highly susceptible to functional and structural destroy after ischemia/reperfusion (I/R), thereby contributing to myocardial energy insufficiency and cardiomyocyte death. Fas-activated serine/threonine kinase (FASTK) is recently recognized as a key modulator of mitochondrial gene expression and respiration. However, the role of FASTK in cardiac I/R process is undetermined. Here, we show that FASTK expression was down-regulated in the post-I/R heart. The reactive oxygen species scavenger N-acetyl-L-cysteine reversed I/R-induced FASTK down-regulation. Genetic deletion of FASTK exacerbated I/R-induced cardiac dysfunction, enlarged myocardial infarct size, and increased cardiomyocyte apoptosis. Compared with the wild type control, the FASTK deficient heart exhibited a lower mRNA expression of NADH dehydrogenase subunit-6 (MTND6, a mitochondrial gene encoding a subunit of complex I) and was more vulnerable to I/R-associated complex I inactivation. Replenishment of FASTK expression via adenovirus-mediated gene delivery restored mitochondrial complex I activity and ameliorated cardiomyocyte death induced by I/R, whereas these beneficial effects were blocked by the co-treatment with rotenone, a specific complex I inhibitor. in vivo experiments further confirmed that cardiac overexpression of FASTK ameliorated I/R-related MTND6 down-regulation and mitochondrial complex I inactivation, thereby protecting the heart against I/R injury. Collectively, these data for the first time identify that the down-regulation of FASTK is a direct culprit behind the loss of mitochondrial complex I functional integrity and cardiac injury induced by I/R process. Targeting FASTK might be a promising and effective strategy for MI/R intervention.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Fas-Activated Serine/Threonine Kinase Governs Cardiac Mitochondrial Complex I Functional Integrity in Ischemia/Reperfusion Heart

Chen

Wang

et al. 2021

Front. Cell Dev. Biol.

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“…Phagocytosis of macrophages is also regulated by Fas 48. Fas-activated serine/threonine kinase (FASTK) negatively regulates phagocytosis of bacteria by macrophages 49. Although FAS induced by ENVs is involved in cell apoptosis, our data suggest that ENVs do not induce apoptosis of macrophages which can be explained by the reduction of CD36, another apoptosis-related protein 50.…”

Section: Discussionmentioning

confidence: 74%

Tumor-derived nanovesicles promote lung distribution of the therapeutic nanovector through repression of Kupffer cell-mediated phagocytosis

Qiu¹,

Li²,

Han³

et al. 2019

Theranostics

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Tumor-derived nanovesicles have been widely used as a biomarker or therapeutic target in various tumor types. However, these nanovesicles have limited use in therapy due to the risk of advancing tumor development. Methods : Exosome-like nanovesicles (ENVs) were developed from metastatic breast cancer 4T1 cells-derived exosomes. The distribution of ENVs and their impact on macrophage-mediated phagocytosis were evaluated. The effect of ENVs pretreatment on anti-lung metastasis therapeutic effects of chemotherapeutic drugs delivered by DOTAP/DOPE liposomes in breast cancer-bearing mice was also examined. Results : We demonstrated that, following intravenous injection in mice, ENVs were preferentially uptaken by Kupffer cells and repressed phagocytosis. The decreased uptake appeared to be due to the translocation of membrane nucleolin from the inner face of the plasma membrane to the cell surface and intercellular Ca 2+ fluxes, leading to altered expression of genes involved in phagocytosis by macrophages. Mice pretreated with 4T1-derived ENVs led to the decreased uptake of DOTAP: DOPE liposomes (DDL) in the liver. Consequently, doxorubicin-loaded DDL transported to the lungs instead of the liver, effectively inhibiting breast cancer lung metastasis. Importantly, 4T1 cells exosome-derived ENVs had no detectable toxicity in vivo and low-risk to promote tumor growth and metastasis compared to 4T1 cells exosomes. Conclusion : Our results suggested that pretreatment with 4T1 ENVs represents a strategy to escape Kupffer cell-mediated phagocytosis effectively targeting drug delivery vehicles to tumor metastasis, reducing the IC 50 of the chemotherapeutic drugs, and avoiding adverse side effects.

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“…The KCNN4 gene is functionally operational, being present in synovial fibroblasts associated with RA, and plays a role in controlling cell growth and the secretion of harmful and pro-inflammatory substances 50 . NDUFS3, a pro-oxidant component of electron transport chain (ETC) complex I, regulates nonopsonic phagocytosis of bacteria in macrophages 51 . Although the exact cause of NDUFS3 in RA remains uncertain, certain research has indicated its role in the progression of various conditions, including systemic lupus erythematosus (SLE) and lung adenocarcinoma (LUAD) 52 , 53 .…”

Section: Discussionmentioning

confidence: 99%

Unveiling the link between lactate metabolism and rheumatoid arthritis through integration of bioinformatics and machine learning

Yang,

Shen,

Zhao

et al. 2024

Sci Rep

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Rheumatoid arthritis (RA) is a persistent autoimmune condition characterized by synovitis and joint damage. Recent findings suggest a potential link to abnormal lactate metabolism. This study aims to identify lactate metabolism-related genes (LMRGs) in RA and investigate their correlation with the molecular mechanisms of RA immunity. Data on the gene expression profiles of RA synovial tissue samples were acquired from the gene expression omnibus (GEO) database. The RA database was acquired by obtaining the common LMRDEGs, and selecting the gene collection through an SVM model. Conducting the functional enrichment analysis, followed by immuno-infiltration analysis and protein–protein interaction networks. The results revealed that as possible markers associated with lactate metabolism in RA, KCNN4 and SLC25A4 may be involved in regulating macrophage function in the immune response to RA, whereas GATA2 is involved in the immune mechanism of DC cells. In conclusion, this study utilized bioinformatics analysis and machine learning to identify biomarkers associated with lactate metabolism in RA and examined their relationship with immune cell infiltration. These findings offer novel perspectives on potential diagnostic and therapeutic targets for RA.

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The Mitochondrial Isoform of FASTK Modulates Nonopsonic Phagocytosis of Bacteria by Macrophages via Regulation of Respiratory Complex I

Cited by 8 publications

References 46 publications

Fas-Activated Serine/Threonine Kinase Governs Cardiac Mitochondrial Complex I Functional Integrity in Ischemia/Reperfusion Heart

Fas-Activated Serine/Threonine Kinase Governs Cardiac Mitochondrial Complex I Functional Integrity in Ischemia/Reperfusion Heart

Tumor-derived nanovesicles promote lung distribution of the therapeutic nanovector through repression of Kupffer cell-mediated phagocytosis

Unveiling the link between lactate metabolism and rheumatoid arthritis through integration of bioinformatics and machine learning

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