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Mitochondrial gene expression is required for platelet function and blood clotting

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE206543 | GEO | 2023/10/03

REPOSITORIES: GEO

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Mitochondrial gene expression is required for platelet function and blood clotting

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

Platelet-secreted microRNA-223 promotes endothelial cell apoptosis induced by advanced glycation end products via targeting the insulin-like growth factor 1 receptor

Project description:Platelets contain abundant miRNAs, however, the biogenesis pathway of miRNAs in anucleate platelets is unclear. Platelet-rich plasma was diluted in washing buffer and the platelet suspension was centrifuged to isolated pure platelets.Finally, platelets were recovered in suspension buffer at the concentration of 4–5×10^8 platelets/ml. Aliquots of the platelet suspensions were activated in the presence of 2.5 mM CaCl2 with 0ng/ml or 1 ng/ml thrombopoietin (TPO)

2014-02-04 | E-GEOD-51453 | biostudies-arrayexpress

Expression data from human platelets after purification

Project description:Platelets are small anucleate cells derived from the fragmentation of megakaryocytes and are involved in different biological processes especially hemostasis, thrombosis and immune response. Platelet purification is a crucial step in transcriptomic analysis, and researchers usually encounter the problem of platelet contamination by leukocytes and erythrocytes. Leukocytes contain much more RNA than platelets, thus the presence of few contaminants in platelet preparation can strongly alter transcriptome results. Using microarray technique, we compared transcriptome of platelets from the same donor, purified by common centrifugation method or using magnetic microbeads to eliminate contaminating cells.

2022-03-31 | GSE193664 | GEO

Platelet factor 4 (PF4) is induced by klotho and rejuvenates cognition and its molecular signature in the aging hippocampus

Project description:Platelet factors regulate wound healing and also signal from the blood to the brain. However, whether platelet factors modulate cognition, a highly valued and central manifestation of brain function, is unknown. Here, we show that systemic platelet factor 4 (PF4) modulates cognition and its molecular signature. Klotho, a longevity and cognition-enhancing protein, acutely activated platelets and increased circulating platelet factors, most robustly platelet factor 4 (PF4). To directly test PF4 effects on the brain, we treated mice with vehicle or systemic PF4. In young mice, PF4 enhanced synaptic plasticity and cognition. In aging mice, PF4 restored cognitive deficits and rejuvenated a molecular signature of cognition in the aging hippocampus. Augmenting platelet factors such as PF4, a possible messenger of klotho, may enhance cognition in the young brain and rejuvenate cognitive deficits in the aging brain.

2023-06-24 | GSE171929 | GEO

Platelet-secreted microRNA-223 promotes endothelial cell apoptosis induced by advanced glycation end products via targeting the insulin-like growth factor 1 receptor

Project description:Platelets contain abundant miRNAs, however, the biogenesis pathway of miRNAs in anucleate platelets is unclear.

2014-02-04 | GSE51453 | GEO

Gene expression analysis of THP-1 cells co-cultured with platelet-like particles

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

Gene expression analysis of THP-1 cells co-cultured with platelet-like particles

2012-05-18 | GSE38027 | GEO

Young blood-derived platelet factors abate inflammation and rescue recognition in aging.

Project description:We show that platelet factors transfer rejuvenating effects of young plasma to the aging brain. Proteomic analysis of plasma from young and aged mice identified age-related changes in platelets. Systemic exposure of aged animals to the platelet fraction of young plasma decreased hippocampal neuroinflammation at a transcriptional and cellular level and ameliorated cognitive impairments. We identified the platelet-derived chemokine CXCL4/Platelet Factor-4 (PF4) as a pro-youthful circulating factor. Systemic PF4 administration decreased age-related neuroinflammation, restored the aging peripheral immune system to a more youthful state, and improved hippocampal-dependent learning and memory in aged mice.

2023-06-20 | GSE173254 | GEO

RNA sequencing of primary human platelets and in vitro cell lines

Project description:Platelets are anucleate cytoplasmic fragments that lack genomic DNA, but continue to synthesize protein using a pool of mRNAs, ribosomes, and regulatory small RNAs inherited from the precursor megakaryocyte (MK). The regulatory processes that shape the platelet transcriptome and the full scope of platelet translation have remained elusive. Using RNA-Seq and ribosome profiling of primary human platelets, we show the platelet transcriptome encompasses a subset of transcripts detected by RNA-Seq analysis of in vitro derived MK cells and these platelet-enriched transcripts are broadly occupied by ribosomes. We use RNA sequencing of synchronized populations of in vitro derived platelet-like particles (PLPs) to show that mRNA decay strongly shapes the nascent platelet transcriptome. Our data suggests that the decay of platelet mRNAs is slowed by the natural loss of the mRNA surveillance and ribosome rescue factor Pelota (PELO).

2017-02-02 | GSE94384 | GEO

Functionally-relevant splicing of resident pre-mRNAs in anucleate platelets upon activation by physiological stimuli

Project description:Platelet activation is the key event triggering thrombus formation in physiological and pathological conditions, such as acute coronary syndromes. Current therapies using antiaggregants still fail to prevent thrombotic coronary events in a significant number of patients, indicating that the mechanisms modulating platelet response during activation need to be clarified. The evidence that platelets are capable of de novo protein synthesis in response to stimuli raised the issue of how the activity of megakaryocyte-derived mRNAs is regulated in these anucleate cell fragments. We applied a combined multi-omics approach to investigate this phenomenon in platelets from healthy donors activated in vitro with Collagen or Thrombin Receptor Activating Peptide. Combining HiRIEF LC-MS to transcriptome analysis by RNA-Seq allowed platelet proteome characterization at deep coverage, revealing a significant effect of either stimulus on proteome composition. In silico intron retention analysis was then applied to search for splicing events induced by platelet activation, coupled to unbiased proteogenomics, to correlate intron retention in resting platelets to intron removal by RNA splicing during activation. This allowed identification of a set of transcripts, specifically involved in platelet shape changes, showing reduced intron retention and high peptide representation at exon-exon junctions in activated vs resting platelets. These results indicate that RNA splicing events takes place in platelets during activation and that pre-mRNA maturation of specific transcripts is part of the activation cascade and could therefore provide novel molecular markers of platelet activation status in acute coronary syndromes and other pathological conditions.

2018-01-15 | E-MTAB-6148 | biostudies-arrayexpress

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