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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

2020-11-15 | GSE107058 | GEO

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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Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC

Project description:High metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contribute to therapy resistance, necessitating identification of novel therapeutic vulnerabilities. Here, we identify non-canonical functions of the ECM remodeler, lysyl oxidase (LOX), in regulating glucose metabolism and mitochondrial homeostasis and show that inhibiting LOX generates targetable vulnerability to ferroptosis. Mechanistically, LOX interacts with PARKIN and its upstream kinase PINK1, which we identified as a substrate of LOX. LOX-mediated PINK1 oxidation suppresses PARKIN phosphorylation, stabilizing HIF-1α and increasing glycolysis. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and maintains mitochondria-ER contacts through VDAC1 stabilization while the LOX-HSP90 complex promotes mitochondrial Ca2+ transport and ATP production. Inhibiting LOX suppresses glycolysis, disrupts mitochondrial dynamics, reduces OXPHOS and GPX4/FSP1, and induces compensatory DHODH activity. Our ‘one-two punch’ approach combining LOX inhibition with clinical DHODH inhibitor suppresses tumor growth in vivo in chemo-free setting. Notably, LOX protein correlates with HIF-1α/GLUT1/GPX4 in TNBC patient tumors, supporting its clinical relevance.

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

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

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Lysyl oxidase (LOX) inhibition creates vulnerability to ferroptosis by disrupting mitochondrial homeostasis in TNBC

Project description:High degree of metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contributes to its aggressiveness and resistance to standard therapies, necessitating identification of novel therapeutic vulnerabilities. Here, we identify previously unrecognized, non-canonical functions of ECM remodeler, lysyl oxidase (LOX), in coupling glucose metabolism with mitophagy and redox homeostasis, and show that inhibiting LOX generates a targetable vulnerability to ferroptosis, an iron-mediated cell death. Mechanistically, LOX directly interacts with PARKIN and its upstream kinase PINK1, which we identified as a novel LOX substrate. LOX-mediated PINK1 oxidation prevents PARKIN phosphorylation, preventing HIF-1α proteasomal degradation, increasing glycolysis. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and triggers mitochondria-ER contacts via preventing VDAC1 proteasomal degradation, while the LOX-HSP90 complex promotes mitochondrial CA2+ transport. Inhibiting LOX disrupts mitochondrial dynamics, reduces OXPHOS and antioxidant GPX4/FSP1, while triggering compensatory DHODH activity in a mitophagy-dependent manner. Our ‘one-two punch’ approach combining LOX inhibitor or shLOX with clinical DHODH inhibitor, leflunomide, leads to strong tumor growth inhibition in multiple in vivo models in a chemo-free setting. Notably, LOX protein correlates with HIF-1α/GLUT1/GPX4 in patient tumors. Together, we present LOX as a therapeutic target, inducing vulnerability to ferroptosis in TNBC.

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2007-06-28 | E-GEOD-4113 | biostudies-arrayexpress

Arabidopsis plants with altered levels of alternative oxidase

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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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Mitochondrial OGG1 expression reduces age-associated neuroinflammation by regulating cytosolic mitochondrial DNA

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