Autophagic regulation of platelet biology

Luo, Xuling; Jiang, Jinyong; Huang, Zhen; Chen, Linxi

doi:10.1002/jcp.28243

Cited by 11 publications

(4 citation statements)

References 56 publications

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“…In this study, increased levels of LC3B were observed, which suggested the occurrence of autophagy in the platelets of SFTS patients. Complete autophagic ux, from the formation of autophagosomes to autophagic degradation, is important for the number, size, and activation of platelets and could be a potential therapeutic target for hemorrhagic and thrombosis diseases [55]. Moreover, upregulated autophagy in platelets promotes platelet activation by decreasing hemostasis and thrombus formation [55], which reduce the number of platelets and shorten the lifespan of platelets [56].…”

Section: Discussionmentioning

confidence: 99%

“…Complete autophagic ux, from the formation of autophagosomes to autophagic degradation, is important for the number, size, and activation of platelets and could be a potential therapeutic target for hemorrhagic and thrombosis diseases [55]. Moreover, upregulated autophagy in platelets promotes platelet activation by decreasing hemostasis and thrombus formation [55], which reduce the number of platelets and shorten the lifespan of platelets [56]. Whether SFTSV infection induces complete autophagic ux in human platelets needs to be veri ed.…”

Section: Discussionmentioning

confidence: 99%

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RNA transcriptome analysis of platelets revealed altered platelet responses and the mechanism of thrombocytopenia in SFTS

Fang,

Zhang,

et al. 2023

Preprint

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Background Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne viral hemorrhagic fever disease caused by infection with Dabie bandavirus (SFTS virus, SFTSV). Thrombocytopenia is the primary clinical feature of SFTS and is significantly associated with disease severity. However, the pathological mechanism of thrombocytopenia in SFTS remains unclear. Methods Platelets purified from SFTS patients were subjected to RNA transcriptome analyses. Differentially expressed genes (DEGs) in the platelets of deceased and surviving patients were identified, and their functions and transcription levels were characterized. DEGs related to cell death were compared with the platelets of COVID-19 and dengue fever patients. The percentage of platelets positive for biomarkers of pyroptosis, apoptosis, necroptosis, autophagy, and ferroptosis was determined by flow cytometry. RNA transcriptome analyses were also performed with platelets purified from nonlethal SFTSV infection model mice. DEGs representing the functional changes in mouse platelets were characterized, and platelet death was also investigated. Functional platelet changes in SFTS patients and SFTSV-infected mice were compared to determine the different mechanisms underlying thrombocytopenia in humans and mice. Results Platelet transcriptome analyses revealed altered platelet functioning in SFTS patients and suggested an active platelet response in surviving patients but not in fatal patients. Enhanced neutrophil activation, interferon (IFN) signaling, and the virus life cycle were common platelet responses in SFTS. The increased histone methylation and impaired vesicle organization in platelets may be related to the fatal outcome, while the enhanced protein transport to membrane and RNA catabolic process may contribute to disease recovery. Moreover, SFTSV infection resulted in platelet loss via pyroptosis, apoptosis, necroptosis, and autophagy but not ferroptosis. Unlike platelets in SFTS patients, platelets in SFTSV-infected mice play a role mainly in regulating adaptive immunity, and platelet death in mice was not as severe as that in humans. Conclusions This study revealed altered platelet functioning in response to SFTSV infection and the mechanisms of thrombocytopenia in humans, which are different from those in mice infected with SFTSV. The results deepen our understanding of the pathogenesis of thrombocytopenia in SFTS and provides insights for subsequent studies on SFTS pathogenesis and the development of novel intervention strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

RNA transcriptome analysis of platelets revealed altered platelet responses and the mechanism of thrombocytopenia in SFTS

Fang,

Zhang,

et al. 2023

Preprint

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“…The latest study showed that P2RY12 receptor inhibits autophagy and reduces cholesterol e uence, promoting VSMC-derived foam cytogenic in advanced atherosclerosis (22). In addition, autophagy has been stated to play an essential role in bleeding and thrombotic diseases by regulating the count and function of PLT, which are the core factors of physiological hemostasia (23). Therefore, it is necessary to conduct clinical or basic experiments to probe the underlying biological functions of these DEARGs.…”

Section: Discussionmentioning

confidence: 99%

Identification and Experimental Validation of Autophagy-Related Genes in Abdominal aortic aneurysm

Yuan

Song

Hai

et al. 2022

Preprint

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Aim Autophagy plays essential roles in abdominal aortic aneurysm (AAA) happening and movement. The objective of this study was to verify the autophagy-related genes (ARGs) underlying AAA empirically and using bioinformatics analysis. Methods Two gene expression profile datasets (GSE98278 and GSE57691) were taken from the GEO database. These datasets were combined and then standardized. The underlying differential expression autophagy-related genes (DEARGs) of AAA were tested using R software. PPIs, associativity, GO enrichment and KEGG pathway functional analyses were used to identify the DEARGs. Finally, qRT-PCR was used to identify the RNA expression levels of the top five hub genes in clinical samples. Results In data from 97 AAA patients and 10 healthy controls, a total of 44 DEARGs (6 up-regulated expressed genes and 38 down-regulated expressed genes) were classified. PPI results showed that these ARGs interact. GO and KEGG enrichment analyses were directed to elucidate the bio-functional of DEARGs. qRT-PCR results presented that the expressed of IL6, PPARG, SOD1 and MAP1LC3B in AAA cases and negative control were in accordance with the bioinformatic analysis results. Conclusion Hub genes such as IL6, PPARG, SOD1 and MAP1LC3B may influence the happening of AAA by controlling autophagy. These findings enhance interpretation of AAA and may be helpful in its diagnosis and treatment.

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“…13 Mitochondrial autophagy, also called mitophagy, is a selective process that delivers damaged mitochondria into autophagosomes for lysosomal degradation. [14][15][16][17][18][19][20][21][22][23][24] Currently, Parkin/PINK1 (phosphatase and tensin homolog-induced putative kinase 1)-mediated mitophagy and receptor-mediated mitophagy are considered 2 major mitophagy pathways in yeast and mammalian cells. [25][26][27][28] Specifically, upon the loss of mitochondrial membrane potential, PINK1 becomes stabilized and accumulates on the outer mitochondrial membrane, resulting in phosphorylation of ubiquitin and Parkin and the recruitment of autophagy receptors.…”

Section: Introductionmentioning

confidence: 99%

Nix-mediated mitophagy regulates platelet activation and life span

Zhang

Siraj

et al. 2019

Blood Advances

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Key Points• Nix controls platelet activation/arterial thrombosis, regulating platelet mitochondria quality/activity in (patho)physiological settings.• Knockout of Nix increases the life span of platelets by inhibiting autophagic degradation of the mitochondrial protein Bcl-xL. Platelet activation requires fully functional mitochondria, which provide a vital energy source and control the life span of platelets. Previous reports have shown that both general autophagy and selective mitophagy are critical for platelet function. However, the underlying mechanisms remain incompletely understood. Here, we show that Nix, a previously characterized mitophagy receptor that plays a role in red blood cell maturation, also mediates mitophagy in platelets. Genetic ablation of Nix impairs mitochondrial quality, platelet activation, and FeCl 3 -induced carotid arterial thrombosis without affecting the expression of platelet glycoproteins (GPs) such as GPIb, GPVI, and a IIb b 3 . Metabolic analysis revealed decreased mitochondrial membrane potential, enhanced mitochondrial reactive oxygen species level, diminished oxygen consumption rate, and compromised adenosine triphosphate production in Nix 2/2 platelets. Transplantation of wildtype (WT) bone marrow cells or transfusion of WT platelets into Nix-deficient mice rescued defects in platelet function and thrombosis, suggesting a platelet-autonomous role (acting on platelets, but not other cells) of Nix in platelet activation. Interestingly, loss of Nix increases the life span of platelets in vivo, likely through preventing autophagic degradation of the mitochondrial protein Bcl-xL. Collectively, our findings reveal a novel mechanistic link between Nix-mediated mitophagy, platelet life span, and platelet physiopathology. Our work suggests that targeting platelet mitophagy Nix might provide new antithrombotic strategies.

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Autophagic regulation of platelet biology

Cited by 11 publications

References 56 publications

RNA transcriptome analysis of platelets revealed altered platelet responses and the mechanism of thrombocytopenia in SFTS

RNA transcriptome analysis of platelets revealed altered platelet responses and the mechanism of thrombocytopenia in SFTS

Identification and Experimental Validation of Autophagy-Related Genes in Abdominal aortic aneurysm

Nix-mediated mitophagy regulates platelet activation and life span

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