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OMA1, DELE1 and HRI relay mitochondrial stress to the mammalian integrated stress response

ABSTRACT: OMA1, DELE1 and HRI relay mitochondrial stress to the mammalian integrated stress response

PROVIDER: PRJNA557038 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9850540.fastq.gz	Fastqsanger.gz
	SRR9850550.fastq.gz	Fastqsanger.gz
	SRR9850541.fastq.gz	Fastqsanger.gz
	SRR9850551.fastq.gz	Fastqsanger.gz
	SRR9850532.fastq.gz	Fastqsanger.gz

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OMA1, DELE1 and HRI relay mitochondrial stress to the mammalian integrated stress response

Project description:The goal of this study is to understand how mamalian cells respond to the mitochondial stress. Using Quant-seq, we identifed an integrated stress response signature in the cells with compromized mitochondria. Furthermore, using an unbiased CRISPRi genetic screen, we uncovered a novel signaling pathway, in which OMA1, DELE1 and HRI are three major players that relay the mitochondrial stress to the integated stress response. To further study the cellular response in the absence of this pathway, we again used Quant-seq to uncover alternative pathways that might play a role during the mitochondrial stress response.

2019-07-29 | GSE134986 | GEO

mtDNA breaks compromise mitochondrial membrane ultrastructure and trigger an integrated stress response

Project description:Mitochondrial DNA (mtDNA) breaks are deleterious lesions that lead to degradation of mitochondrial genomes and subsequent reduction in mtDNA copy number. The signaling pathways activated in response to mtDNA damage remain ill-defined. Using mitochondrial targeted restriction enzymes, we show that cells with mtDNA breaks exhibit reduced respiratory complexes, loss of membrane potential, and mitochondrial protein import defect. Furthermore, mtDNA damage activates the integrated stress response (ISR) through phosphorylation of eIF2α by the OMA1-DELE1-HRI pathway. Electron microscopy reveals concomitant defects in mitochondrial membranes and cristae ultrastructure. Notably, inhibition of the ISR exacerbates mitochondrial defects and delays the recovery of mtDNA copy number, thereby implicating this stress response in mitigating mitochondrial dysfunction following mtDNA damage. Last, we provide evidence suggesting that ATAD3A, a membrane-anchored protein that interacts with nucleoids, relays the signal from mtDNA breaks to the inner mitochondrial membrane. Altogether, our study fully delineates the sequence of events linking damaged mitochondrial genomes with the cytoplasm and uncovers an unanticipated role for the ISR in response to mitochondrial genome instability.

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Gene expression profile at Ptpmt1 cardiomyocytes-specific Knockout mcie, Eif2a mutant mice, Gcn2 Knockout mice, and Hri Knockout mice

Project description:To study the mitochondrial stress response HRI-eIF2a-ATF4 signaling pathway in mitochondrial cardiomyopathy , we generated Ptpmt1 cardiomyocytes-specific Knockout mcie, Eif2a mutant mcie, Gcn2 Knockout mcie, and Hri Knockout mcie

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Iron and Heme Coordinate Erythropoiesis through HRI-Mediated Regulation of Protein Translation and Gene Expression

Project description:Iron and heme play central roles in red blood cell production. However, the mechanisms by which iron and heme levels coordinate erythropoiesis remain incompletely understood. HRI is a heme-regulated kinase that controls translation by phosphorylating eIF2a. Here, we investigate the global impact of iron, heme and HRI on protein translation in vivo in murine primary erythroblasts using ribosome profiling. By defining the underlying changes in translation during iron and HRI deficiencies, we validate known regulators of this process, including Atf4, and identify novel pathways such as co-regulation of ribosomal protein mRNA translation. Surprisingly, we found that heme and HRI pathways, but not iron-regulated pathways, mediate the major protein translational and transcriptional responses to iron deficiency in erythroblasts in vivo and thereby identify previously unappreciated regulators of erythropoiesis. Our genome-wide study uncovers the major impact of the HRI-mediated integrated stress response for the adaptation to iron deficiency anemia.

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mtDNA breaks compromise mitochondrial membrane ultrastructure and trigger an integrated stress response

Project description:Mitochondrial DNA (mtDNA) breaks are toxic lesions that lead to degradation of mitochondrial genomes and subsequent reduction in mtDNA copy number. The signaling pathways activated in response to mtDNA damage remain poorly understood. We reasoned that factors that sense mtDNA damage are likely to be recruited to nucleoids shortly after break formation, prompting us to develop a proteomic-based approach to survey the interactome of mitochondrial nucleoids. Specifically, we combined proximity-dependent biotin labeling with Stable Isotope Labeling by Amino acids in Cell culture (SILAC) and tandem mass spectrometry. We used mitochondrial targeted restriction enzymes for the proximity probe and show that cells with mtDNA breaks exhibit reduced respiratory complexes, loss of membrane potential, and mitochondrial protein import defect. Notably, mtDNA breaks activate the integrated stress response (ISR) through phosphorylation of eIF2a by the OMA1-DELE1-HRI pathway. Inhibition of the ISR exacerbates mitochondrial defects and delays the recovery of mtDNA copy number, hinting at a role for the ISR in mitigating mitochondrial dysfunction following mtDNA damage. Electron microscopy reveals defective mitochondrial membranes and cristae ultrastructure. Last, we highlight a potential role for ATAD3A - a protein that is anchored to the inner mitochondrial membrane while interacting with nucleoids - in relaying the signal from damaged mtDNA to the mitochondrial inner membrane. Altogether, our study delineates the sequence of events linking damaged mitochondrial genomes to the cytoplasmic stress response. The mass spectrometry raw files for the combined SILAC and proximity-dependent biotin labeling experiment are deposited here.

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HRI depletion cooperates with pharmacologic inducers to elevate fetal hemoglobin and reduce sickle cell formation

Project description:Increasing fetal hemoglobin (HbF) provides clinical benefit in patients with sickle cell disease (SCD). We recently identified heme-regulated inhibitor (HRI, EIF2AK1) as a novel HbF regulator. Since HRI is an erythroid-specific protein kinase it presents a potential target for pharmacologic intervention. We find that maximal HbF induction requires >80-85% HRI depletion. As it remains unclear whether this degree of HRI inhibition can be achieved pharmacologically, we explored whether HRI knockdown can be combined with pharmacologic HbF inducers to achieve greater HbF production and minimize potential adverse effects associated with treatments. Strongly cooperative HbF induction was observed when HRI depletion was combined with exposure to pomalidomide or the EHMT1/2 inhibitor UNC0638, but not hydroxyurea. Mechanistically, reduction in the levels of the HbF repressor BCL11A reflected the cooperativity of HRI loss and pomalidomide treatment, whereas UNC0638 did not modulate BCL11A levels. In conjunction with HRI loss, pomalidomide maintained its HbF inducing activity at 10-fold lower concentrations, at which condition there were minimal observed detrimental effects on erythroid cell maturation and viability as well as fewer alterations in the erythroid transcriptome. In sum, this study provides a foundation for the exploration of combining future small molecule HRI inhibitors with additional pharmacologic HbF inducers to maximize HbF production and preserve erythroid cell functionality for the treatment of SCD and other hemoglobinopathies.

2020-09-21 | GSE150341 | GEO

Serratia sp. HRI

Project description:Serratia sp. HRI Genome sequencing and assembly

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Domain-focused CRISPR-screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells

Project description:Increasing fetal hemoglobin (HbF) levels in adult red blood cells provides clinical benefit to patients with sickle cell disease and some forms of beta-thalassemia. To identify potentially druggable HbF regulators in adult human erythroid cells, we employed a protein kinase-domain focused CRISPR/Cas9-based genetic screen with a newly optimized sgRNA scaffold. The screen uncovered the heme-regulated inhibitor HRI (also known as EIF2AK1), an erythroid-specific kinase that controls protein translation, as an HbF repressor. HRI depletion markedly increased HbF production in a specific manner and reduced sickling in cultured erythroid cells. Diminished expression of the HbF repressor BCL11A accounted in large part for the effects of HRI depletion. Taken together, these results suggest HRI as a potential therapeutic target for hemoglobinopathies.

2018-07-20 | GSE115687 | GEO

A MITOCHONDRIAL STRESS RESPONSE TRIGGERED BY DEFECTS IN PROTEIN SYNTHESIS QUALITY CONTROL

Project description:Quality control defects of mitochondrial nascent chain synthesis trigger a sequential stress response characterised by OMA1 activation and ribosome decay, determining mitochondrial form and function.

2019-01-23 | PXD012416 | Pride

HRI activates ATF4 to promote BCL11A transcription and fetal hemoglobin silencing [Capture-C]

Project description:Through a CRISPR-Cas9 guided loss-of-function screen in human erythroid cells we identified transcription factor ATF4, a known HRI-regulated protein, as a novel γ-globin repressor. ATF4 binds to a BCL11A enhancer to augment promoter contacts, stimulates BCL11A transcription to repress γ-globin expression. Notably, mice deficient for HRI displayed normal Bcl11a levels, suggesting species selective regulation that we explain here by demonstrating that the analogous ATF4 motif at the murine Bcl11a enhancer is largely dispensable. This illustrates potential limits of commonly used murine models of globin gene regulation.

2020-04-17 | GSE143962 | GEO

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