Inflammation causes remodeling of mitochondrial cytochrome
            <i>c</i>
            oxidase mediated by the bifunctional gene
            <i>C15orf48</i>

Clayton, Sally A.; Daley, K.; MacDonald, Lucy; Fernández-Vizarra, Erika; Bottegoni, Giovanni; O’Neil, John D.; Major, Triin; Griffin, Daniel Patrick; Zhuang, Qinqin; Adewoye, Adeolu B.; Woolcock, Kieran; Jones, Simon W.; Goodyear, Carl S.; Elmesmari, Aziza; Filer, Andrew; Tennant, Daniel A.; Alivernini, Stefano; Buckley, Christopher D.; Pitceathly, Robert D S; Kurowska‐Stolarska, Mariola; Clark, Andrew R.

doi:10.1126/sciadv.abl5182

Cited by 45 publications

(46 citation statements)

References 81 publications

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“…One explanation for this discrepancy could be that these studies lack matched tumor adjacent tissue to correlate their findings. Conversely, low expression of SELL (CD62L) and CXCR2 (both downregulated in aged neutrophils (Lin et al, 2020)) and high expression of the known neutrophil activation markers CD83 (an inhibitory immune checkpoint) (Li et al, 2019; Yamashiro et al, 2000), the atypical chemokine receptor CCRL2 (Del Prete et al, 2017), ICAM1 (CD54) (Lin et al, 2020) , C15orf48 (a mitochondrial transcript upregulated during inflammation) (Clayton et al, 2021) as well as several cytokines ( CCL3, CCL4, CXCL2) (Figure S5B) support an aged/chronically activated/exhausted TAN phenotype (Zhang et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

High-resolution single-cell atlas reveals diversity and plasticity of tissue-resident neutrophils in non-small cell lung cancer

Salcher

Sturm

Horvath

et al. 2022

Preprint

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SUMMARYNon-small cell lung cancer (NSCLC) is characterized by molecular heterogeneity with diverse immune cell infiltration patterns, which has been linked to both, therapy sensitivity and resistance. However, full understanding of how immune cell phenotypes vary across different patient and tumor subgroups is lacking. Here, we dissect the NSCLC tumor microenvironment at high resolution by integrating 1,212,463 single-cells from 538 samples and 309 patients across 29 datasets, including our own dataset capturing cells with low mRNA content. Based on the cellular composition we stratified patients into immune deserted, B cell, T cell, and myeloid cell subtypes. Using bulk samples with genomic and clinical information, we identified specific cellular components associated with tumor histology and genotypes. Analysis of cells with low mRNA content uncovered distinct subpopulations of tissue-resident neutrophils (TRNs) that acquire new functional properties in the tissue microenvironment, providing evidence for the plasticity of TRNs. TRN-derived gene signature was associated with anti-PD-L1 treatment failure in a large NSCLC cohort.In briefSalcher, Sturm, Horvath et al. integrate single-cell datasets to generate the largest transcriptome atlas in NSCLC, refining patient stratification based on tumor immune phenotypes, and revealing associations of histological subtypes and genotypes with specific cellular composition patterns.Coverage of cells with low mRNA content by single-cell sequencing identifies distinct tissue-resident neutrophil subpopulations, which acquire new properties within the tumor microenvironment. Gene signature from tissue-resident neutrophils is associated with immune checkpoint inhibitor treatment failure. The integrated atlas is publicly available online (https://luca.icbi.at), allowing the dissection of tumor-immune cell interactions in NSCLC.HighlightsHigh-resolution single-cell atlas of the tumor microenvironment (TME) in NSCLC.Histological tumor subtypes and driver genes imprint specific cellular TME patterns.scRNA-seq of cells with low transcript count identifies distinct tissue-resident neutrophil (TRN) subpopulations and non-canonical functional properties in the TME niche.TRN gene signature identifies patients who are refractory to treatment with PD-L1 inhibitors.Abstract Figure

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Section: Resultsmentioning

confidence: 99%

High-resolution single-cell atlas reveals diversity and plasticity of tissue-resident neutrophils in non-small cell lung cancer

Salcher

Sturm

Horvath

et al. 2022

Preprint

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“…In addition, HSPA8 has been shown to be an attachment factor for the avian infectious bronchitis coronavirus (Zhu et al, 2020). C15orf48 expression, on the other hand, has been shown to be involved in the mitochondrial stress response (MISTR) and is expressed by pathogenic macrophages in severe COVID-19 (Liao et al, 2020; Clayton et al, 2021). Interestingly, IFI27 and IFIT3 are also involved with the mitochondrial processes; the former locates in the nuclear inner membrane and is indispensable for mitochondrial function (Jin et al, 2018) and the latter is mediator of the mitochondrial antiviral signaling (MAVS) complex triggered by the MDA-5 and RIG-I signaling pathways (Liu et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Single-cell RNA-sequencing data analysis reveals a highly correlated triphasic transcriptional response to SARS-CoV-2 infection

Sánchez

Elena

2022

Preprint

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Single-cells RNA sequencing (scRNA-seq) is currently one of the most powerful techniques available to study the transcriptional response of cells to external perturbations. However, the use of conventional bulked RNA-seq analysis methods can miss important patterns underlying in the scRNA-seq data. Here, we present a reanalysis of scRNA-seq data from human bronchial epithelial cells and colon and ileum organoids using pseudo-time profiles based on the degree of virus accumulation which reflect the progress of infection. Our analysis revealed a transcriptional response to infection characterized by three distinct up- and down-regulatory phases, that cannot be detected using classical two-group comparisons. Interrogation of results, focused on genes involved in interferon-response, transcription factors and RNA-binding proteins, suggests a highly correlated transcriptional response for most genes. In addition, correlation network analysis revealed a distinct response of genes involved in translation and mitochondrially-encoded genes. Based on our data, we propose a model where modulation of nucleocytoplasmic traffic by the viral protein nsp1 explains the triphasic transcriptional response to SARS-CoV-2 infection.

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“…The expression of C15orf48 transcript is positively correlated with disease severity in patients with rheumatoid arthritis. In addition, macrophages from human patients genetically lacking NDUFA4, a subunit of CIV, exhibit hyperinflammatory characteristics, independent from changes in cellular ATP production rates, again underscoring the complex relationship between the function of respiration and its component parts ( 30 ). Our findings identify a regulatory modality that controls availability and function of SDHB protein during the early pro-inflammatory macrophage response, thereby tuning the activity of CII.…”

Section: Discussionmentioning

confidence: 97%

“…Although observations using pharmacological inhibition must be interpreted with caution, the preponderance of data support that components of the respiratory complexes are prime targets for multi-level regulation. In addition to alterations in transcript or protein levels, Clayton et al, determined that in response to inflammatory signals, the Cytochrome c oxidase (C c O) subunit NDUFA4, is replaced by a paralogous component, C15ORF48 ( 30 ). The expression of C15orf48 transcript is positively correlated with disease severity in patients with rheumatoid arthritis.…”

Section: Discussionmentioning

confidence: 99%

Cardiolipin coordinates inflammatory metabolic reprogramming through regulation of Complex II assembly and stability

Reynolds

Hong

Michmerhuizen

et al. 2022

Preprint

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Macrophage metabolic plasticity enables repurposing of electron transport from energy generation to inflammation and host defense. Altered Respiratory Complex II function has been implicated in cancer, diabetes and inflammation but regulatory mechanisms are incompletely understood. Here we show that macrophage inflammatory activation triggers Complex II disassembly and succinate dehydrogenase-B subunit loss through sequestration and mitophagy. Mitochondrial fission was required for lipopolysaccharide-stimulated succinate dehydrogenase-B degradation but not sequestration. We hypothesized that this Complex II regulatory mechanism might be coordinated by the mitochondrial phospholipid cardiolipin. Cardiolipin synthase knockdown prevented lipopolysaccharide-induced metabolic remodeling and Complex II disassembly, sequestration and degradation. Cardiolipin-depleted macrophages were defective in lipopolysaccharide-induced pro-inflammatory cytokine production, a phenotype partially rescued by Complex II inhibition. Thus, cardiolipin acts as a critical organizer of inflammatory metabolic remodeling.

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Inflammation causes remodeling of mitochondrial cytochrome c oxidase mediated by the bifunctional gene C15orf48

Abstract: Exchange of mitochondrial subunits C15ORF48 and NDUFA4 occurs during macrophage activation in vitro and in inflammatory disease.

Cited by 45 publications

References 81 publications

High-resolution single-cell atlas reveals diversity and plasticity of tissue-resident neutrophils in non-small cell lung cancer

High-resolution single-cell atlas reveals diversity and plasticity of tissue-resident neutrophils in non-small cell lung cancer

Single-cell RNA-sequencing data analysis reveals a highly correlated triphasic transcriptional response to SARS-CoV-2 infection

Cardiolipin coordinates inflammatory metabolic reprogramming through regulation of Complex II assembly and stability

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