Critical role for the mitochondrial permeability transition pore and cyclophilin D in platelet activation and thrombosis

Jobe, Shawn M.; Wilson, Katina M.; Leo, Lorie; Raimondi, Alejandro; Molkentin, Jeffery D.; Lentz, Steven R.; Paola, Jorge Di

doi:10.1182/blood-2007-05-092684

Cited by 186 publications

(264 citation statements)

References 46 publications

Supporting

Mentioning

240

Contrasting

Unclassified

Order By: Relevance

“…26,27 In this context, the procoagulant platelet response is distinct from all other physiologic platelet activation responses, in that it is primarily initiated by cell death pathways that produce fundamental alterations in platelet morphology, ultrastructure and function.…”

Section: Perspectives and Future Directionsmentioning

confidence: 99%

“…Consistent with this, platelet CypD deficiency markedly reduces agonist-induced loss of mitochondrial membrane potential (⌬ m ) and platelet procoagulant function. 27 Moreover, ROS production is elevated in platelets undergoing high, sustained cytosolic Ca 2ϩ flux, 28,29 and H 2 O 2 has been demonstrated to promote platelet procoagulant function through a CypD-dependent mechanism. 27 Whether ROS is responsible for undermining the integrity of the lysosomal and platelet plasma membranes remains to be established, 2,30 nonetheless there is a correlation between platelet lysosomal enzyme activity and procoagulant activity.…”

Section: Functional Necrosismentioning

confidence: 99%

“…27 Moreover, ROS production is elevated in platelets undergoing high, sustained cytosolic Ca 2ϩ flux, 28,29 and H 2 O 2 has been demonstrated to promote platelet procoagulant function through a CypD-dependent mechanism. 27 Whether ROS is responsible for undermining the integrity of the lysosomal and platelet plasma membranes remains to be established, 2,30 nonetheless there is a correlation between platelet lysosomal enzyme activity and procoagulant activity. 30 Consistent with a necrotic process, calpains (not caspases) play the major role in disassembling the cytoskeleton and promoting the release of procoagulant microvesicles from the surface of platelets.…”

Section: Functional Necrosismentioning

confidence: 99%

“…However, while high levels of Ca 2ϩ appear to be a prerequisite for SCIP formation, this is not always the case for COATED platelets, as treatment of platelets with Ca 2ϩ ionophore does not lead to fibrinogen retention. 27 Given the acronyms of COAT, COATED platelets, 35 and SCIP reflect only specific aspects of platelet procoagulant function, it may be more appropriate to classify agonist-induced procoagulant platelets (those that have undergone a high, sustained cytosolic calcium response) as procoagulant necrotic platelets (Table 1), a term that may more accurately reflect the underlying molecular processes governing the cell's fate. In this model, anucleate circulating platelets possess finite amounts of BclXL, Bak, and Bax.…”

Section: Procoagulant Platelets: Searching For Their Real Identitymentioning

confidence: 99%

See 3 more Smart Citations

Procoagulant platelets: are they necrotic?

Jackson

Schoenwaelder

2010

Blood

141

View full text Add to dashboard Cite

Apoptosis and necrosis represent distinct cell death processes that regulate mammalian development, physiology and disease. Apoptosis characteristically leads to the silent destruction and removal of cells in the absence of an inflammatory response. In contrast, necrotic cell death can induce physiologic inflammatory responses linked to tissue defense and repair. Although anucleate, platelets undergo programmed cell death, with apoptosis playing an important role in clearing effete platelets from the circulation. While it has long been recognized that procoagulant platelets exhibit characteristic features of dying cells, recent studies have demonstrated that platelet procoagulant function can occur independent of apoptosis. A growing body of evidence suggest that the biochemical, morphologic and functional changes underlying agonist-induced platelet procoagulant function are broadly consistent with cell necrosis, raising the possibility that distinct death pathways regulate platelet function and survival. In this article, we will discuss the mechanisms underlying apoptotic and necrotic cell death pathways and examine the evidence linking these pathways to the platelet procoagulant response. We will also discuss the potential contribution of these pathways to the platelet storage lesion and propose a simplified nomenclature to describe procoagulant platelets. IntroductionUntil the early 1970s it was thought that all cells die as a result of necrosis (Table 1); a form of cell death that is prominent when tissues undergo extensive damage from trauma or disease. This concept changed dramatically in 1972 after the landmark observations of Kerr and colleagues, 9 who described a new form of cell death, termed apoptosis (Table 1). Since then, the genetic and biochemical processes responsible for apoptotic cell death have been extensively investigated. It is now well defined that apoptosis is a key process underlying human development, normal physiology and a range of common human diseases. 10 In contrast, the concepts underlying necrosis have become less clear-cut. While it has long been assumed that necrosis is predominantly a pathologic process resulting from tissue injury, there is growing evidence that cells can orchestrate their own demise through programmed cell necrosis in a manner that initiates physiologic inflammatory and repair responses. [2][3][4][6][7][8] Although anucleate, platelets have the capacity to undergo programmed cell death (Table 1). This has been most clearly demonstrated with platelet apoptosis; a process that is important for clearance of effete platelets from the circulation. 1,11 Many of the features of apoptosis (membrane fragmentation, cytoskeletal disruption, microvesiculation, caspase activation and phosphatidylserine [PS] exposure) are observed during prolonged platelet storage ex vivo and during the conversion of activated platelets to a procoagulant state, raising the possibility that apoptosis may also regulate platelet function. However, recent studies have demonstrated that the m...

show abstract

Section: Perspectives and Future Directionsmentioning

confidence: 99%

Section: Functional Necrosismentioning

confidence: 99%

Section: Functional Necrosismentioning

confidence: 99%

Section: Procoagulant Platelets: Searching For Their Real Identitymentioning

confidence: 99%

See 2 more Smart Citations

Procoagulant platelets: are they necrotic?

Jackson

Schoenwaelder

2010

Blood

141

View full text Add to dashboard Cite

show abstract

“…Along with glycogen granules, platelet mitochondria provide energy that is needed at least indirectly for platelet aggregation and secretion of procoagulant molecules (4). More direct evidence of a role for mitochondria in coagulation rests on observations that changes in the permeability of mitochondrial membranes are linked to changes in coagulation activity (5,6). These facts imply that inhibition of platelet mitochondrial function should have an inhibitory effect upon platelet-activated blood coagulation.…”

mentioning

confidence: 99%

Inhibiting platelet-stimulated blood coagulation by inhibition of mitochondrial respiration

Barile

Herrmann

Tyvoll

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Platelets are important mediators of blood coagulation that lack nuclei, but contain mitochondria. Although the presence of mitochondria in platelets has long been recognized, platelet mitochondrial function remains largely unaddressed. On the basis of a small amount of literature that suggests platelet mitochondria are functional, we hypothesized that the inhibition of platelet mitochondria disrupts platelet function and platelet-activated blood coagulation. To test this hypothesis, members of the tetrazole, thiazole, and 1,2,3-triazole families of small molecule heterocycles were screened for the ability to inhibit isolated mitochondrial respiration and coagulation of whole blood. The families of heterocycles screened were chosen on the basis of the ability of the heterocycle family to inhibit a biomimetic model of cytochrome c oxidase (CcO). The strength of mitochondrial inhibition correlates with each compound's ability to deter platelet stimulation and platelet-activated blood clotting. These results suggest that for this class of molecules, inhibition of blood coagulation may be occurring through a mechanism involving mitochondrial inhibition. Platelets are directly involved in a number of functions necessary for clotting, including recognition of vascular lesions, triggering activation of the coagulation cascade, and activation of other platelets. The platelet membrane serves as a scaffold for clot formation, and platelets are involved in the activation and cocatalysis of reactions involving many of the soluble clotting factors (1). Like red blood cells, platelets lack nuclei and consequently are unable to replace damaged proteins encoded in the nuclear genome. However, unlike red blood cells, platelets contain actively metabolizing mitochondria (2). Some hints as to the role these mitochondria play in platelet function have been elucidated (3). Along with glycogen granules, platelet mitochondria provide energy that is needed at least indirectly for platelet aggregation and secretion of procoagulant molecules (4). More direct evidence of a role for mitochondria in coagulation rests on observations that changes in the permeability of mitochondrial membranes are linked to changes in coagulation activity (5, 6). These facts imply that inhibition of platelet mitochondrial function should have an inhibitory effect upon platelet-activated blood coagulation.Experimental investigation led to the discovery of three families of small molecule heterocycles that reversibly inhibit mitochondrial respiration and attenuate platelet-activated blood coagulation. These three families of compounds comprise unique examples of a class of anticoagulants proposed to inhibit blood clotting through a mitochondrial mechanism (Fig. 1).The discovery of these particular families of platelet inhibitory molecules occurred after initial work from the Collman laboratory related to biomimetic modeling of cytochrome c oxidase (CcO). CcO is the terminal enzyme in the electron transport chain that catalyzes the four-electron reduction of O 2...

show abstract

Phosphatidylserine exposure and other apoptotic‐like events in Bernard‐Soulier syndrome platelets

et al. 2010

View full text Add to dashboard Cite

In the Bernard-Soulier syndrome (BSS), the giant platelets are said to have increased phosphatidylserine (PS) surface exposure in the resting state and shortened survival in the circulation. When normal platelets are activated, they undergo many biochemical and morphological changes, some of which are apoptotic. Herein, we investigated apoptotic-like events in BSS platelets upon activation, specifically, PS exposure, microparticle (MP) formation, cell shrinkage, and loss of mitochondrial inner membrane potential (DC m ). Platelets from two unrelated BSS patients were examined in whole blood; agonists used were collagen, thrombin, PAR1-or PAR4-activating peptides (APs), or combinations of collagen with thrombin, and the PAR-APs. Flow cytometry was used to measure PS exposure (annexin A5 binding), platelet-derived MPs (forward scatter; events <0.75 lm size), and DC m (TMRM fluorescence). PS exposure was increased on resting and activated BSS platelets, and this was independent of the platelet size. MP formation by BSS platelets was generally enhanced. Cell shrinkage occurred on activation to form smaller, PS-exposing platelets in BSS and controls. A proportion of PS-exposing BSS and control platelets exhibited DC m loss, but unlike controls, there was also loss of DC m in the BSS platelets not exposing PS. Thus, BSS platelets undergo apoptotic-like events upon activation, with PS exposure and MP formation being enhanced. These events may play a role in the shortened survival in BSS, as well as affecting thrombin generation. Am. J. Hematol. 85:584-592, 2010. V

show abstract

Critical role for the mitochondrial permeability transition pore and cyclophilin D in platelet activation and thrombosis

Cited by 186 publications

References 46 publications

Procoagulant platelets: are they necrotic?

Procoagulant platelets: are they necrotic?

Inhibiting platelet-stimulated blood coagulation by inhibition of mitochondrial respiration

Phosphatidylserine exposure and other apoptotic‐like events in Bernard‐Soulier syndrome platelets

Contact Info

Product

Resources

About