The mitochondrial signature of cultured endothelial cells in sepsis: Identifying potential targets for treatment

Montero-Jodra, Alba; de la Fuente, Miguel Ángel; Gobelli, Dino; Martín-Fernández, Marta; Villar, Jesús; Tamayo, Eduardo; Simarro, María

doi:10.1016/j.bbadis.2023.166946

Cited by 3 publications

(1 citation statement)

References 110 publications

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“…Growing evidence associates sepsis with a network of dysfunctional processes, including a poorly coordinated immune system response [1]. Sepsis is a serious organ dysfunction that results in millions of fatal cases per year [2].…”

Section: Introductionmentioning

confidence: 99%

Acod1 Mediate Anti-inflammatory Treg Function in Sepsis

Mickael,

Kubick,

Atansov

et al. 2024

Preprint

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Sepsis is a serious disease that can lead to mortality. The etiology of the disease is connected to how the body as a host reacts toward microbes such as bacteria, viruses, and fungi invasion. Current research shows that during sepsis, the reaction toward microbe attacks takes two main phases. The first is known as a cytokine storm, while the second is a vicious cycle of pro-inflammatory responses followed by a strict anti-inflammatory response led by CD4+ Tregs. Various immunomodulatory therapies have been proposed to break the cycle of pro- and anti-inflammatory reactions to sepsis. However, clinical trials did not show promising results, indicating further research into the mechanism that Treg uses to inhibit proinflammatory reactions. We used next-generation sequencing (NGS) analysis of bulk RNA-seq and single-cell RNA-seq data to examine the exact molecular pathways used by Treg to inhibit the immune response in sepsis. Our approach identified ACOD1 (Aconitate Decarboxylase 1) as a primary mediator of Treg suppression of immune cells. We identified and validated CD36 as a downstream target of ACOD1. CD36 is a known metabolite regulator in Tregs. Taken together, our results indicate that targeting ACOD1 could prove valuable in regulating Treg function during sepsis.

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Section: Introductionmentioning

confidence: 99%

Acod1 Mediate Anti-inflammatory Treg Function in Sepsis

Mickael,

Kubick,

Atansov

et al. 2024

Preprint

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Identification of sepsis-associated mitochondrial genes through RNA and single-cell sequencing approaches

Li,

Jiang

et al. 2024

BMC Med Genomics

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Background Sepsis ranks among the most formidable clinical challenges, characterized by exorbitant treatment costs and substantial demands on healthcare resources. Mitochondrial dysfunction emerges as a pivotal risk factor in the pathogenesis of sepsis, underscoring the imperative to identify mitochondrial-related biomarkers. Such biomarkers are crucial for enhancing the accuracy of sepsis diagnostics and prognostication. Methods In this study, adhering to the SEPSIS 3.0 criteria, we collected peripheral blood within 24 h of admission from 20 sepsis patients at the ICU of the Southwest Medical University Affiliated Hospital and 10 healthy volunteers as a control group for RNA-seq. The RNA-seq data were utilized to identify differentially expressed RNAs. Concurrently, mitochondrial-associated genes (MiAGs) were retrieved from the MitoCarta3.0 database. The differentially expressed genes were intersected with MiAGs. The intersected genes were then subjected to GO (Gene Ontology), and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses and core genes were filtered using the PPI (Protein-Protein Interaction) network. Subsequently, relevant sepsis datasets (GSE65682, GSE28750, GSE54514, GSE67652, GSE69528, GSE95233) were downloaded from the GEO (Gene Expression Omnibus) database to perform bioinformatic validation of these core genes. Survival analysis was conducted to assess the prognostic value of the core genes, while ROC (Receiver Operating Characteristic) curves determined their diagnostic value, and a meta-analysis confirmed the accuracy of the RNA-seq data. Finally, we collected 5 blood samples (2 normal controls (NC); 2 sepsis; 1 SIRS (Systemic Inflammatory Response Syndrome), and used single-cell sequencing to assess the expression levels of the core genes in the different blood cell types. Results Integrating high-throughput sequencing with bioinformatics, this study identified two mitochondrial genes (COX7B, NDUFA4) closely linked with sepsis prognosis. Survival analysis demonstrated that patients with lower expression levels of COX7B and NDUFA4 exhibited a higher day survival rate over 28 days, inversely correlating with sepsis mortality. ROC curves highlighted the significant sensitivity and specificity of both genes, with AUC values of 0.985 for COX7B and 0.988 for NDUFA4, respectively. Meta-analysis indicated significant overexpression of COX7B and NDUFA4 in the sepsis group in contrast to the normal group (P < 0.01). Additionally, single-cell RNA sequencing revealed predominant expression of these core genes in monocytes-macrophages, T cells, and B cells. Conclusion The mitochondrial-associated genes (MiAGs) COX7B and NDUFA4 are intimately linked with the prognosis of sepsis, offering potential guidance for research into the mechanisms underlying sepsis.

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Acod1 mediates anti-inflammatory Treg function in sepsis

Mickael,

Kubick,

Atansov

et al. 2024

Animal Science Papers and Reports

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Sepsis is a serious, potentially fatal disease caused by the body’s reaction to microbial invasions by bacteria, viruses, and fungi. Current research shows that the process of fighting sepsis passes through two phases. The first phase is a cytokine storm, and the second phase involves a cycle of pro-inflammatory and anti-inflammatory responses led by Regulatory CD4+ T-cells (CD4+ Tregs). Various immunomodulatory therapies have been proposed to break the cycle of pro- and anti-inflammatory reactions to sepsis. However, clinical trials are yet to show any promising results, indicating the need for further research into the mechanisms behind Treg dysfunction. We used next-generation sequencing (NGS) analysis of five datasets comprising of bulk RNA-seq and single-cell RNA-seq data to explore our research question. Our results identified Acod1 (Aconitate Decarboxylase 1) as a primary mediator of Treg suppression of immune cells as well as various metabolic pathways regulated by IL4 and IL10. scRNA-seq analysis showed that Acod1 and FoxP3 were localised in the same Treg-like cells. Further evidence from our study further suggests a mutual positive regulation loop between Acod1 and FoxP3 in sepsis. Additionally, CD36 was identified as a downstream target of Acod1. CD36 is a known metabolite regulator in Tregs, where it functions as a transporter of long fatty chains (LCFA) and is regulated by IL4 and IL10. Taken together, our results indicate that the metabolic CD36/Acod1 axis could be responsible for the continuous activation of Treg in sepsis. Thus, targeting this axis could prove valuable in improving the sepsis prognosis.

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The mitochondrial signature of cultured endothelial cells in sepsis: Identifying potential targets for treatment

Cited by 3 publications

References 110 publications

Acod1 Mediate Anti-inflammatory Treg Function in Sepsis

Acod1 Mediate Anti-inflammatory Treg Function in Sepsis

Identification of sepsis-associated mitochondrial genes through RNA and single-cell sequencing approaches

Acod1 mediates anti-inflammatory Treg function in sepsis

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