Neuroprotective compounds alter the expression of genes coding for proteins related to mitochondrial function in activated microglia

• Published in: Mitochondrion 2024-09, Vol.78, p.101934, Article 101934
• Main Authors: Serrano-Marín, Joan, Valenzuela, Rita, Delgado, Cristina, Quijano, Aloia, Navarro, Gemma, Labandeira –García, José Luis, Franco, Rafael
• Format: Article
• Language: English
• Subjects: adenosine A2A receptor; adenosine A3 receptor; G-protein-coupled receptors; Mitochondria; Neurodegeneration; Neuroinflammation
• ISSN: 1567-7249; 1872-8278; 1872-8278
• DOI: 10.1016/j.mito.2024.101934

•RNAseq reveals gene expression changes in activated microglia by adenosinergic compounds.•A significant number of genes coding for mitochondrial components were differentially expressed in treated microglia.•Adenosine A2A receptor antagonist improved mitochondrial function in activated microglia.•Adenosinergic compounds increased mitochondrial respiration while reducing the expression of proinflammatory genes. A hallmark of neuroinflammatory disorders is mitochondrial dysfunction. Nevertheless, the transcriptional changes underlying this alteration are not well-defined. Microglia activation, a decrease in mitochondrion biogenesis and a subsequent alteration of the redox are common factors in diseases coursing with neuroinflammation. In the last two decades, components of the adenosinergic system have been proposed as potential therapeutic targets to combat neuroinflammation. In this research, we analyzed by RNAseq the gene expression in activated microglia treated with an adenosine A2A receptor antagonist, SCH 582561, and/or an A3 receptor agonist, 2-Cl-IB-MECA, since these receptors are deeply related to neurodegeneration and inflammation. The analysis was focused on genes related to inflammation and REDOX homeostasis. It was detected that in the three conditions (microglia treated with 2-Cl-IB-MECA, SCH 582561, and their combination) more than 40 % of the detected genes codified by the mitochondrial genome were differentially expressed (FDR 85 %) upregulated in the microglia treated with adenosinergic compounds. Also, we analyzed the differential expression of genes related to mitochondrial function and oxidative stress codified by the nuclear genome. Additionally, we evaluated the oxygen consumption rate (OCR) of mitochondria in microglia treated with LPS and IFN-γ, both alone and in combination with adenosinergic compounds. The data showed an improvement in mitochondrial function with the antagonist of the adenosine A2A receptor, compared to the effects of pro-inflammatory stimulus, confirming a functional effect consistent with the RNAseq data.