MTH1's role in platelet function
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Jianlin Qiao
PROVIDER: PXD041528 | iProX | Fri Apr 14 00:00:00 BST 2023
REPOSITORIES: iProX
Publications
MTH1 protects platelet mitochondria from oxidative damage and regulates platelet function and thrombosis.
Ding Yangyang Y Gui Xiang X Chu Xiang X Sun Yueyue Y Zhang Sixuan S Tong Huan H Ju Wen W Li Yue Y Sun Zengtian Z Xu Mengdi M Li Zhenyu Z Andrews Robert K RK Gardiner Elizabeth E EE Zeng Lingyu L Xu Kailin K Qiao Jianlin J
Nature communications 20230810 1
Human MutT Homolog 1 (MTH1) is a nucleotide pool sanitization enzyme that hydrolyzes oxidized nucleotides to prevent their mis-incorporation into DNA under oxidative stress. Expression and functional roles of MTH1 in platelets are not known. Here, we show MTH1 expression in platelets and its deficiency impairs hemostasis and arterial/venous thrombosis in vivo. MTH1 deficiency reduced platelet aggregation, phosphatidylserine exposure and calcium mobilization induced by thrombin but not by collage ...[more]
Similar Datasets
Project description:Platelets are anucleate blood cells that contain mitochondria, that regulate blood clotting in response to injury. Mitochondria contain their own gene expression machinery which relies on nuclear encoded factors for the biogenesis of the oxidative phosphorylation (OXPHOS) system to produce energy, ions and metabolites required for thrombosis. The autonomy of the mitochondrial gene expression machinery from the nucleus is not known and platelets provide a valuable model to understand the importance of mitochondrial gene expression in anucleate cells. We generated three different platelet-specific conditional knockout mouse models, each lacking a gene that is essential for mitochondrial gene expression at the level of RNA processing, stability and translation (Elac2Pf4∆/Pf4∆, Ptcd1Pf4∆/Pf4 and Mtif3Pf4∆/Pf4∆). Loss of ELAC2, PTCD1 or MTIF3, leads to increased megakaryocyte ploidy, elevated circulating levels of reticulated platelets, thrombocytopenia and consequent extended bleeding time. Loss of ELAC2, PTCD1 and MTIF3 reduced agonist induced platelet activation. Transcriptomic and proteomic analyses showed that mitochondrial gene expression and protein synthesis facilitate fibrinolysis, haemostasis and blood coagulation in response to injury.
2023-10-03 | GSE206543 | GEO
Project description:Platelets are anucleate blood cells that contain mitochondria and regulate blood clotting in response to injury. Mitochondria contain their own gene expression machinery which relies on nuclear encoded factors for the biogenesis of the oxidative phosphorylation (OXPHOS) system to produce energy, ions and metabolites required for thrombosis. The autonomy of the mitochondrial gene expression machinery from the nucleus is not known and platelets provide a valuable model to understand the importance of mitochondrial gene expression in anucleate cells. We generated three different platelet-specific conditional knockout mouse models, each lacking a gene that is essential for mitochondrial gene expression at the level of RNA processing, stability and translation (Elac2Pf4?/Pf4?, Ptcd1Pf4?/Pf4 and Mtif3Pf4?/Pf4?). Loss of ELAC2, PTCD1 or MTIF3, leads to increased megakaryocyte ploidy, elevated circulating levels of reticulated platelets, thrombocytopenia and consequent extended bleeding time. Furthermore, impaired RNA metabolism also reduced agonist induced platelet activation. Transcriptomic and proteomic analyses showed that mitochondrial gene expression and protein synthesis facilitate fibrinolysis, haemostasis and blood coagulation in response to injury.
2023-11-01 | PXD045688 | Pride
Project description:Relationships between platelet mitochondrial oxygen consumption rates (mOCR) and metabolites in platelets as measured by quantitative 1H-NMR metabolomics. Samples collected in ED at a single timepoint. WB and platelets isolated from the same blood samples. Comparison of mitochondrial function and metabolomics in patients with sepsis and non-sepsis ED patients
2019-12-13 | ST001294 | MetabolomicsWorkbench
Project description:Proteasome Function is Required for Platelet Production
| PRJNA251563 | ENA
Project description:Acute myocardial infarction (AMI) is primarily due to coronary atherosclerotic plaque rupture and subsequent thrombus formation. Platelets play a key role in the genesis and progression of both atherosclerosis and thrombosis. Since platelets are anuclear cells that inherit their mRNA from megakaryocyte precursors and maintain it unchanged during their life span, gene expression (GE) profiling at the time of an AMI provides information concerning the platelet GE preceding the coronary event. In ST-segment elevation myocardial infarction (STEMI), a gene-by-gene analysis of the platelet GE identified five differentially expressed genes (DEGs): FKBP5, S100P, SAMSN1, CLEC4E and S100A12. The logistic regression model used to combine the GE in a STEMI vs healthy donors score showed an AUC of 0.95. The same five DEGs were externally validated using platelet GE data from patients with coronary atherosclerosis but without thrombosis. Early signals of an imminent AMI are likely to be found by platelet GE profiling before the infarction occurs.
2019-12-31 | GSE109048 | GEO
Project description:Relationships between platelet mitochondrial oxygen consumption rates (mOCR) and metabolites in platelets as measured by quantitative 1H-NMR metabolomics in WB. Comparison of mitochondrial function and metabolomics in patients with sepsis and non-sepsis ED patients
2019-12-13 | ST001295 | MetabolomicsWorkbench
Project description:The Stem Cell Leukemia (Scl or Tal1) protein forms part of a multimeric transcription factor complex required for normal megakaryopoiesis. However, unlike other members of this complex such as Gata1, Fli1 and Runx1, mutations of Scl have not been observed as a cause of inherited thrombocytopenia. We postulated that functional redundancy with its closely related family member, Lymphoblastic Leukemia 1 (Lyl1) might explain this observation. To determine if Lyl1 can substitute for Scl in megakaryopoiesis, we examined the platelet phenotype of mice lacking one or both factors in megakaryocytes. Conditional Scl knockout mice crossed with transgenic mice expressing Cre recombinase under the control of the mouse platelet factor 4 (Pf4) promoter generated megakaryocytes with markedly reduced but not absent Scl. These Pf4SclcKO mice had mild thrombocytopenia and subtle defects in platelet aggregation. However, Pf4SclcKO mice generated on a Lyl1-null background (double knockout, DKO mice) had severe macrothrombocytopenia, abnormal megakaryocyte morphology, defective pro-platelet formation and markedly impaired platelet aggregation. DKO megakaryocytes, but not single knockouts, had reduced expression of Gata1, Fli1, Nfe2 and many other genes that cause inherited thrombocytopenia. These gene expression changes were significantly associated with shared Scl and Lyl1 E-box binding sites that were also enriched for Gata1, Ets and Runx1 motifs. Thus, Scl and Lyl1 share functional roles in platelet production and function by regulating expression of partner proteins including Gata1 and Fli1. We propose that this functional redundancy provides one explanation for the absence of Scl and Lyl1 mutations as a cause of inherited thrombocytopenia.
2020-12-21 | GSE125025 | GEO
Project description:Hyperlipidemia is a well-established risk factor for cardiovascular diseases. Trillions of people worldwide display mildly elevated levels of plasma lipids and cholesterol due to diet and life-style. The relationship between severe hyperlipidemia and thrombosis has been extensively investigated, but the effects of the preliminary stages of hyperlipidemia on platelet function are unclear. Therefore, we investigated how moderate elevation of different plasma lipid profiles influence platelet activation and thrombus formation, as compared to higher plasma lipid concentrations. Hyperlipidemic Apoe-/- and Ldlr-/- and wild-type mice were fed a normal chow diet, resulting in mildly increased plasma cholesterol. Blood from both knockout mice was used in comparison to wild-type mice, for multiparameter ex vivo measurements of thrombus formation under flow. Whole blood (fibrin-)thrombus formation on collagen in the absence or presence of coagulation (with(out) tissue factor), indicated enhancement of the thrombotic process in both knockout mice. These effects were not further aggravated in aged mice, as well as in Apoe-/- mice on high fat diet with very high plasma cholesterol levels. Bone marrow chimeras of wild-type or Ldlr-/- platelets into irradiated Ldlr-/- recipient mice showed similar thrombus formation patterns. This suggested that hyperlipidemia itself, not the platelet LDL receptor deficiency is responsible for the altered platelet activation status in Ldlr-/- mice. Exploration of the platelet proteome revealed high similarity between the three genotypes, although some proteins showed significantly changed expression in Apoe-/- mice. Finally, platelet lipidomic analysis showed an increased lipid profile in mildly hyperlipidemic mice, which may further contribute to the observed prothrombotic phenotype
2021-01-08 | PXD020276 | Pride
Project description:For the anucleate platelet it has been unclear how well platelet transcriptomes correlate among different donors or across different RNA profiling platforms, and what the transcriptomes’ relationship is with the platelet proteome. We generated RNA-seq pro-files of the long RNA transcriptomes from the platelets of 10 healthy young males (5 white and 5 black) with median age of 24.5 years, no notable clinical history, and no pre-vious history of thrombosis or bleeding. We also profiled the subjects’ messenger RNAs using the Affymetrix microarray gene expression system. We found that the abundance of platelet mRNA transcripts was highly correlated across the 10 individuals, inde-pendently of race and of the employed technology. Our RNA-seq data also showed that these high inter-individual correlations extend beyond mRNAs to several categories of non-coding RNAs. Pseudogenes represented a notable exception to this by exhibiting a clear difference in expression by race. Comparison of our mRNA signatures with the only publicly available quantitative platelet proteome data showed that most (87.5%) identified platelet proteins had a detectable corresponding mRNA. However, a high number of mRNAs that were present in the transcriptomes of all 10 individuals had no representa-tion in the proteome. The Spearman correlation of the relative abundances for those platelet genes that were represented by both an mRNA and a protein showed a weak (~0.3) yet statistically significant (P=5.0E-16) connection. Further analysis of the overlap-ping and non-overlapping platelet mRNAs and proteins identified gene groups corre-sponding to distinct cellular processes, a finding that provides novel insights for platelet biology. This represents the Affymetrix GeneChip component of the study only 10 Resting Human Platelet samples
2015-01-20 | E-GEOD-50858 | biostudies-arrayexpress
Project description:Abstract. The role of platelets in hemostasis and thrombosis is clearly established; however, the mechanisms by which platelets mediate inflammatory and immune pathways are less well understood. Platelets interact and modulate the function of blood and vascular cells by releasing bioactive molecules. Although the platelet is anucleate, it contains transcripts that may mirror disease. Platelet mRNA is only associated with low-level protein translation, however, platelets have a unique membrane structure allowing for the passage of small molecules, leading to the possibility that its’ cytoplasmic RNA may be passed to nucleated cells. To examine this question, platelet-like particles with labeled RNA were co-cultured with vascular cells. Co-culture of platelet-like particles with activated THP-1, monocytic, and endothelial cells led to visual and functional RNA transfer. Post-transfer microarray gene expression analysis of THP-1 cells showed an increase in HBG1/HBG2 and HBA1/HBA2 expression which was directly related to the transfer. Infusion of wild-type platelets into a TLR2 deficient mouse model established in vivo confirmation of select platelet RNA transfer to leukocytes. By specifically transferring green fluorescent protein, it was also observed that external RNA was functional in the recipient cells. The observation that platelets possess the capacity to transfer cytosolic RNA suggests a new function for platelets in the regulation of vascular homeostasis. THP-1, treated with Pam3CSK4, were co-cultured with platelet-like particles for 12 hours and 24 hours then collected and processed for RNA isolation. We also included as control THP-1 untreated and THP-1 treated with Pam3CSK4. A total of 4 samples were analyzed by microarray for gene expression.
2012-05-17 | E-GEOD-38027 | biostudies-arrayexpress