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RNA microarray studies of aspirin's effect on MnSOD-deficient mutant [EG110, (MT)] and wild-type [EG103, (WT)] Saccharomyces cerevisiae yeast cells

ABSTRACT: Non-steroidal anti-inflammatory drugs, principally aspirin (acetylsalicylic acid, ASA), have anti-neoplastic properties, as shown by epidemiological studies on colorectal cancer and many other types of tumours. The chemopreventive and anti-proliferative properties of aspirin towards tumour cells have been shown to be due to the induction of programmed cell death such as apoptosis. Yeast cells are among the experimental models used extensively for the study of oxidative stress and apoptosis in living organisms because yeast, such as S. cerevisiae, retains many of the core eukaryotic cellular processes, including the hallmarks of eukaryotic apoptosis. An important contribution of our previous work has been the clarification of the critical defensive role of the antioxidant mitochondrial enzyme manganese superoxide dismutase (MnSOD) against apoptosis, confirmed to be the attenuation of aspirin-induced superoxide radical accumulation in the yeast mitochondria (Farrugia et al. (2013) FEMS Yeast Res 13, 755-768). To study the possible differential expression of gene transcripts in relation to the induction of apoptosis by aspirin, we used gene expression profiling by means of GeneChip® Microarray Technology (Affymetrix®). The yeast strains considered for this study included (1) the wild type strain S. cerevisiae EG103, which contains both MnSOD and cytosolic copper, zinc superoxide dismutase (CuZnSOD) and (2) the redox-compromised MnSOD-deficient S. cerevisiae EG110 strain. [This work was financed by the Malta Council for Science and Technology through the R&I Technology Development Programme (Project R&I-2015-001)].

ORGANISM(S): Saccharomyces cerevisiae Schizosaccharomyces pombe

PROVIDER: GSE115660 | GEO | 2019/01/31

REPOSITORIES: GEO

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Project description:This study aims to investigate the role and mechanism of DEK in asthmatic airway inflammation and in regulating PTEN-induced putative kinase 1 (PINK1)-Parkin mediated mitophagy, NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome activation, and apoptosis. We found that recombinant DEK protein (rmDEK) promoted eosinophils recruitment, mitochondrial fragmentation, and outer membrane 20 (TOM20) and LC3 co-localization representing mitophagosomes in bronchoalveolar lavage fluid (BALF) in house dust mite (HDM) induced-asthma. rmDEK also reduced co-localization of mitochondrial fusion protein mitofusin1 (MFN1) and mitochondria, and the protein level of manganese superoxide dismutase (MnSOD), enhanced microtubule-associated protein1 light chain 3 (LC3) and voltage-dependent anion channels (VDAC) co-localization which also represent the mitophagosomes in airway epithelial cells, furthermore, increased dynamin-related protein 1 (DRP1) expression, PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. In the DEK knockout mice, HDM induced asthmatic airway inflammation, MnSOD, PINK1-Parkin protein level, Parkin mediated mitophagy characterized by LC3 and Parkin co-localization in the airways, ROS generation, NLRP3 inflammation and apoptosis were fully reversed. Similar effects of rmDEK were also observed in the BEAS-2B cells, which were rescued by the autophagy inhibitor 3-MA. Moreover, DEK silencing diminished the Parkin, LC3, DRP1 translocation to mitochondria; as well as mitochondrial ROS; TOM20 and mitochondrial DNA mediated mitochondrial oxidative damage. ChIP-sequence analysis showed that DEK was enriched on the AAA domain-containing protein 3A (ATAD3A) promoter and could positively regulate ATAD3A expression. Additionally, ATAD3A was highly expressed in HDM-induced asthma models. Furthermore, ATAD3A interacted with DRP1, and knockdown of ATAD3A could down-regulate DRP1 and mitochondrial oxidative damage. Conclusively, DEK deficiency alleviates airway inflammation in asthma by down-regulating PINK1-Parkin mitophagy, NLRP3 inflammasome activation, and apoptosis. The mechanism may be through the DEK/ATAD3A/DRP1 signaling axis. Our findings may provide new potential therapeutic targets for asthma treatment.

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RNA microarray studies of aspirin's effect on MnSOD-deficient mutant [EG110, (MT)] and wild-type [EG103, (WT)] Saccharomyces cerevisiae yeast cells

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