Inhibiting the Mitochondrial Sulfhydryl Oxidase ALR reduces levels of Mitochondrial COX17 and induces Differentiation of AML Cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE107058 | GEO | 2020/11/15
REPOSITORIES: GEO
Similar Datasets
Project description:Inhibiting the Mitochondrial Sulfhydryl Oxidase ALR reduces levels of Mitochondrial COX17 and induces Differentiation of AML Cells
| PRJNA418927 | ENA
Project description:Leukemic stem cells (LSC) rely on oxidative metabolism and are differentially sensitive to targeting mitochondrial pathways, which spares normal hematopoietic cells. A subset of mitochondrial proteins are folded in the intermembrane space via the mitochondrial intermembrane assembly (MIA) pathway. We found increased mRNA expression of MIA pathway substrates in acute myeloid leukemia (AML) stem cells. Therefore, we evaluated the effects of inhibiting this pathway in AML. Genetic and chemical inhibition of ALR reduces AML growth and viability, disrupts LSC self-renewal and induces their differentiation. ALR inhibition preferentially decreases its substrate COX17, a mitochondrial copper chaperone and knockdown of COX17 phenocopies ALR loss. Inhibiting ALR and COX17 increases mitochondrial copper levels which in turn inhibit S-Adenosylhomocysteine Hydrolase (SAHH) and lower levels of S-adenosylmethionine (SAM), DNA methylation, and chromatin accessibility to lower LSC viability. These results provide insight into mechanisms through which mitochondrial copper controls epigenetic status and viability of LSCs.
2020-04-14 | GSE146252 | GEO
Project description:Current evidence suggests that nuclear-encoded mitochondrial proteins can be locally translated at the mitochondrial surface and co-translationally or post-translationally imported into mitochondria. mRNA localization on the mitochondrial membrane, a prerequisite for localized translation, remains uncharacterized in higher eukaryotic organisms. We employed fractionation-sequencing to profile mitochondria-associated mRNAs in zebrafish larvae. Our transcriptome-wide analysis reveals the localization of mRNAs of only 12% of the nuclear-encoded mitochondrial proteins to the mitochondrial surface, which suggests that post-translational import is the dominant mode of protein import to mitochondria. Additionally, the mRNAs which were localized to the mitochondrial membrane consisted mostly of those encoding proteins involved in mitochondrial dynamics, suggesting their site-specific translation. Finally, we show that the loss of function of the MIA pathway responsible for the post-translational import of a subclass of mitochondrial proteins, triggers mitochondrial localization of mRNAs encoding proteins that are imported to mitochondria via other pathways. Thus, our study suggests that mRNA targeting and localized translation could be relevant in higher eukaryotes to combat stress conditions affecting mitochondrial biogenesis in general.
2023-10-28 | GSE160355 | GEO
Project description:The vast majority of the mitochondrial proteome originates from nuclear genes and is transported into the organelle after synthesis in the cytosol. Complex machineries, which maintain the specificity of protein import and sorting exist. Dysfunctions of mitochondrial protein sorting pathways result in diminishing specific substrate proteins, followed by systemic pathology of the organelle and organismal death. Cellular responses that are caused by slowdown in the transport of mitochondrial proteins are unknown. Here we have used RNA-seq transcription profiling of Saccharomyces cerevisiae to uncover the changes in the cellular transcriptome in the response to mitochondrial protein import dysfunction caused by mutation in the MIA40 gene. Mia40 is a key component of the mitochondrial intermembrane import and assembly (MIA) pathway. Mia40-4int mutant used in this study is not viable at high temperatures, while in the low, permissive temperature it expresses growth rate comparable to the wild-type strain. Even during the permissive temperature culture mutant cells are characterized by decreased accumulation of MIA substrate proteins. Thus permissive growth conditions were used in the present experiment to emphasise primary responses to mitochondrial protein import defect.
2015-07-31 | E-MTAB-3588 | biostudies-arrayexpress
Project description:Augmenter of liver regeneration (ALR) is a critical multi-isoform protein with its longer isoform, located in the mitochondrial intermembrane space, being part of the mitochondrial disulfide relay system (DRS). Upregulation of ALR was observed in multiple forms of cancer, among them hepatocellular carcinoma (HCC). To shed light into the ALR role in the DRS in HCC, we thus pharmacologically inhibited ALR, resulting in profound mitochondrial impairment and cancer cell proliferation deficits. These effects were mostly reversed by supplementation with bioavailable hemin b, linking the DRS, and specifically ALR function, to mitochondrial iron homeostasis. Since tumor cells are known for their increased iron demand and since increased iron levels in cancer are associated with poor clinical outcome, these results help to further advance the intricate relation between iron and mitochondria in liver cancer.
2022-02-17 | PXD026695 | Pride
Project description:Adult male and female w1118 flies were inflicted with traumatic brain injury using high-impact trauma device. Brains were dissected at control, 1, 2 and 4 hours post-TBI and exposed to near-infrared (NIR) light at 750 nm for 2 hours. Total RNA was extracted from fly brains and 3'mRNA-seq was performed to assess gene expression changes in response to TBI and NIR eposure in both sexes. 3 replicates were sequenced for each condition.
2021-03-16 | GSE158061 | GEO
Project description:Analysis of ALR-deficient cells indicates that ALRs are not required for the IFN response to intracellular DNA. To explore whether AIM2-like receptors activated another innate signaling pathway upon DNA detection, we performed microarray analysis comparing ALR+/+, ALR-/-, and AIM2-/- macrophages and fibroblasts 4 or 8 hours after transfection with calf-thymus DNA. Total RNA was isolated from ALR+/+, ALR-/-, and AIM2-/- bone marrow-derived macrophages (BMMs) or fibroblasts (MEFs) mock-treated (lipofectamine alone) or transfected with 5ug CT-DNA for 4 or 8 hours.
2016-05-31 | E-GEOD-80766 | biostudies-arrayexpress
Project description:Tafazzin (TAZ) is a mitochondrial transacylase that remodels the mitochondrial cardiolipin into its mature form. Through a CRISPR screen, we identified TAZ as necessary for the growth and viability of acute myeloid leukemia (AML) cells. Genetic inhibition of TAZ reduced stemness and increased differentiation of AML cells both in vitro and in vivo. In contrast, knockdown of TAZ did not impair normal hematopoiesis under basal conditions. Mechanistically, inhibition of TAZ decreased levels of cardiolipin but also altered global levels of intracellular phospholipids, including phosphatidylserine, which controlled AML stemness and differentiation by modulating toll-like receptor (TLR) signaling.
| S-EPMC7137093 | biostudies-literature
Project description:Previous studies have shown that dexamethasone (Dex) reduces the levels of anti-nuclear (ANA) and anti-dsDNA antibodies in MRL/lpr mice (a mouse model of SLE). However, the effect of Dex on T follicular helper (Tfh) cells is less documented. Here, using the MRL/lpr mouse model, we investigated the influence of Dex on Tfh cells and potential underlying mechanisms. The data showed that the proportion of Tfh cells, identified as CD4+ CXCR5+ ICOS+ , CD4+ CXCR5+ PD-1+ or CD4+ BCL-6+ cells, markedly decreased after treatment with the Dex, in both Balb/c mice and MRL/lpr mice. Dex significantly inhibited IL-21 expression at both the mRNA and the protein levels. Dex also significantly reduced the proportion of germinal centre B cells and decreased serum IgG, IgG2a/b and IgA levels. Moreover, a positive correlation between the proportion of Tfh cells (CD4+ CXCR5+ ICOS+ , CD4+ CXCR5+ PD-1+ or CD4+ BCL-6+ ) and autoantibodies was observed. Dex significantly increased the Prdm1 and Stat5b mRNA expression and decreased the Bcl-6 and c-Maf mRNA expression of CD4+ T cells. In brief, Dex inhibited the Tfh development, which relies on many other transcription factors in addition to Bcl-6. Our data indicate that Dex can be used as a Tfh cell inhibitor in SLE.
| S-EPMC8419171 | biostudies-literature
Project description:The effects of rosiglitazone (RSG) in patients with type 2 diabetes mellitus (T2DM) remain controversial. Here, we first used network pharmacology to identify the common targets of RSG in the treatment of diabetes angiopathy (DA). Enrichment analysis found that the common genes were involved in the inflammatory response, leukocyte cell-cell adhesion, mitochondrion organization and oxidative stress. Our previous research confirmed that heat shock protein 22 (HSP22) suppresses diabetes-induced endothelial activation and injury by inhibiting mitochondrial reactive oxygen species (mtROS) formation and dysfunction. We then constructed HSP22 knockout mice with T2DM to investigate whether RSG protected the vascular endothelium by upregulating HSP22. Our study suggested that RSG reduced vascular endothelial cell activation and injury by decreasing monocyte adhesion and cytokine secretion and simultaneously upregulating HSP22 expression. Mechanistically, RSG inhibited mitochondrial oxidative stress and dysfunction by regulating PPAR-γ in a manner partially dependent on expression of HSP22, resulting in reduced DA.
| S-EPMC10031002 | biostudies-literature