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Inhibiting the Mitochondrial Sulfhydryl Oxidase ALR reduces levels of Mitochondrial COX17 and induces Differentiation of AML Cells

ABSTRACT: Inhibition of the MIA pathway of mitochindrial protein import by targeting ALR depletes mitochondrial Cox17 and induces differentiation in AML cells

ORGANISM(S): Homo sapiens

PROVIDER: GSE107058 | GEO | 2020/11/15

REPOSITORIES: GEO

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Inhibiting the Mitochondrial Sulfhydryl Oxidase ALR reduces levels of Mitochondrial COX17 and induces Differentiation of AML Cells

Project description:Inhibiting the Mitochondrial Sulfhydryl Oxidase ALR reduces levels of Mitochondrial COX17 and induces Differentiation of AML Cells

| PRJNA418927 | ENA

Disrupting mitochondrial copper distribution inhibits leukemic stem cell self-renewal

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

Profiling of mRNA localization of nuclear-encoded mitochondrial proteins in zebrafish.

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

Comparative analysis of transcripts from mia40-4int mutant and wild-type Saccharomyces cerevisiae strains quantified in RNA-seq experiment

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

Inhibition of the mitochondrial disulfide relay system impairs liver cancer cell proliferation

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

Inhibiting mitochondrial Cytochrome c oxidase downregulates gene transcription after traumatic brain injury in Drosophila

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

Transcriptional response to intracellular DNA in cells lacking AIM2-like receptors

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

The Mitochondrial Transacylase, Tafazzin, Regulates for AML Stemness by Modulating Intracellular Levels of Phospholipids.

Project description: Not available

| S-EPMC7137093 | biostudies-literature

Dexamethasone reduces autoantibody levels in MRL/lpr mice by inhibiting Tfh cell responses.

Project description: Not available

| S-EPMC8419171 | biostudies-literature

mitoCPR - a surveillance pathway that protects mitochondria in response to mitochondrial import stress

Project description:Mitochondrial functions are essential for cell viability and rely on protein import into the organelle. Various disease and stress conditions can lead to mitochondrial import defects. We find that inhibition of mitochondrial import in budding yeast activates a surveillance mechanism, mitoCPR, that is aimed at ameliorating mitochondrial import and protecting mitochondria during import stress. mitoCPR induces expression of Cis1 which associates with the mitochondrial translocase to reduce the accumulation of mitochondrial precursor proteins at the organelle surface. Clearance of precursor proteins depends on the Cis1 interacting AAA+ ATPase Msp1 and the proteasome suggesting that Cis1 facilitates degradation of un-imported proteins at the mitochondrial surface.

2018-04-20 | GSE107784 | GEO

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