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

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

PROVIDER: PRJNA418927 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6303053_1.fastq.gz	Fastqsanger.gz
	SRR6303053_2.fastq.gz	Fastqsanger.gz
	SRR6303054_1.fastq.gz	Fastqsanger.gz
	SRR6303054_2.fastq.gz	Fastqsanger.gz
	SRR6303055_1.fastq.gz	Fastqsanger.gz

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

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

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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.

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

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

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2022-02-17 | PXD026695 | Pride

A First-in-Class Pan-Lysyl Oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer

Project description:The lysyl oxidase family represents a promising target in stromal targeting of solid tumours due to the importance of this family in cross-linking and stabilising fibrillar collagens, and its known role in tumour desmoplasia. Using small-molecule drug design approaches, we generated and validated PXS-5505, a first-in-class, highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumour desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumour perfusion, and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, whilst also demonstrating anti-fibrotic effects in human PDX models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of the first pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma.

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Irp2 mediates cigarette smoke-induced bronchitis and emphysema via regulation of cytochrome c oxidase and mitochondrial iron loading.

Project description:Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death globally, is influenced by both cigarette smoking and genetic determinants. We have previously identified iron-responsive element binding protein 2 (IRP2) as a candidate COPD susceptibility gene based on genetic association studies, with IRP2 increased in the lungs of COPD patients. Here we demonstrate that mice deficient in IRP2 are protected from cigarette smoke (CS)-induced COPD. Using RIP-Seq, RNA-Seq, gene expression and pathway analysis, we identify IRP2 as a regulator of mitochondrial function in the lung. We show that an increase in IRP2 results in a cytochrome c oxidase (COX)-dependent alteration in oxidative capacity and mitochondrial-iron dysfunction involving frataxin. We demonstrate that mice with impaired COX or frataxin activity have altered responses to CS and show that overexpressing IRP2 in vivo alters mitochondrial dynamics. These data suggest a critical role of the mitochondria-iron axis in mediating the pathogenesis of COPD. We used microarrays to compare the global programme of gene expression in the lungs of WT mice compared ot the lungs harvested from Irp2-/- mice. n=6 Wildtype C57/BL6 mice (n=3 males, 3 females), n=5 (n=2 males, n =3 females) Irp2-/- C57/BL6 mice, approx 28-32 weeks were sacrificied, lungs removed and snap forzen. RNA isolated after one freeze thaw cycle using the Qiagen RNeasy Kit.

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Irp2 mediates cigarette smoke-induced bronchitis and emphysema via regulation of cytochrome c oxidase and mitochondrial iron loading

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