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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2496-2497. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bozza, F. A. Articles by Weyrich, A. S. Search for Related Content PubMed Articles by Bozza, F. A. Articles by Weyrich, A. S. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS Comment on Jobe et al in the February 1 issue of Blood, page 1257 Mitochondria push platelets past their prime Fernando A. Bozza, and Andrew S. Weyrich FUNDAÇÃO OSWALDO CRUZ; UNIVERSITY OF UTAH In the February 1 issue of Blood, Jobe and colleagues elucidated the function of the mitochondrial permeability transition pore (MPTP), in platelet activation and demonstrated that cyclophilin D (CypD), a regulator of MPTP formation, is a critical factor in the procoagulant response to strong agonists. Historical roles for platelet mitochondria have been limited to supplying energy for aggregation and secretion. This view, however, continues to be refined and advanced as new functions for this old organelle emerge. It is now well accepted that mitochondria contribute to apoptosis, a process associated with cell death in nucleated cells and recently ascribed to platelets. Mitochondrial membrane potential (m) is reduced in platelets that display apoptotic features,1 and perturbations in the m have been observed in subsets of activated platelets that have high procoagulant activity.2 Although a reproducible phenomenon, it is generally surmised that compromises in mitochondrial integrity are the consequence of irreversible platelet activation that culminates in cell death. In the February 1 issue of Blood, Jobe and colleagues shed new light on these preconceived notions by demonstrating that formation of the mitochondrial permeability transition pore (MPTP) regulates early platelet activation events such as phosphatidylserine externalization, fibrinogen retention, and membrane vesiculation (see figure). View larger version (90K): [in this window] [in a new window]   CypD-dependent MPTP formation plays a critical role in pushing a subset of moderately activated platelets into a highly activated state. Highly activated platelets are more likely to be cleared from the circulation, retract clots at a slower rate, and possess procoagulant activity.   MPTP-dependent platelet activation requires cyclophilin D (CypD), a mitochondrial matrix protein that works together with the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocator (ANT) to modulate m (see figure). Although the functional significance of MPTP-dependent platelet activation is not yet known, it appears that MPTP formation pushes a subset of activated platelets past their prime and into a highly activated state. This CypD-dependent transition is regulated by both the quantity and type of agonist(s) used to activate platelets.1,2 In other words, high concentrations of thrombin or combinations of agonists such as thrombin and H2O2 induce the highly activated phenotype. The fate of highly activated platelets remains undefined, but excessive activation may trigger clearance and thereby contribute to thrombocytopenia, which often occurs in clinical disorders such as sepsis and disseminated intravascular coagulation. High concentrations of thrombin, which are generated in severe sepsis, induce de novo expression of proapoptotic proteins including Bak and Bax,1 and Mason et al3 recently demonstrated that an intrinsic program for apoptosis controls platelet survival and clearance. Thus, pharmacological agents that affect MPTP formation may prove useful in the treatment of diseases that are associated with increased peripheral destruction of apoptotic platelets. Similar interventions may also have value in preventing defects in banked platelets that progressively lose their m and become apoptotic during storage.4 The surprising findings of Jobe and colleagues continue to highlight the resourcefulness of platelets and raise several new possibilities regarding the function of mitochondria in these anucleate cytoplasts. As an example, it is not a foregone conclusion that highly activated platelets are immediately destined for cell death. Indeed, the authors demonstrate that CypD-dependent responses in platelets can regulate clot retraction, a prolonged process that may contribute to vessel recanalization in vivo. Mitochondrial-dependent signals may also affect thrombus growth, as suggested by the authors, and variations in the potential to form highly activated platelets may identify subjects at increased thrombotic risk. Other questions remain, including identification of the signaling pathways that link MPTP formation with early platelet activation responses. Regardless of the outcome, it is clear that we are merely on the cusp of discovering new functions for mitochondria in platelets. Footnotes Conflict-of-interest disclosure: The authors declare no competing financial interests. REFERENCES Leytin V, Allen DJ, Mykhaylov S, Lyubimov E, Freedman J. Thrombin-triggered platelet apoptosis. J Thromb Haemost 2006; 4:2656–2663.[CrossRef][Medline] [Order article via Infotrieve] Remenyi G, Szasz R, Friese P, Dale GL. Role of mitochondrial permeability transition pore in coated-platelet formation. Arterioscler Thromb Vasc Biol 2005; 25:467–471.[Abstract/Free Full Text] Mason KD, Carpinelli MR, Fletcher JI, et al. Programmed anuclear cell death delimits platelet life span. Cell 2007; 128:1173–1186.[CrossRef][Medline] [Order article via Infotrieve] Verhoeven AJ, Verhaar R, Gouwerok EG, de Korte D. The mitochondrial membrane potential in human platelets: a sensitive parameter for platelet quality. Transfusion 2005; 45:82–89.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Critical role for the mitochondrial permeability transition pore and cyclophilin D in platelet activation and thrombosis Shawn M. Jobe, Katina M. Wilson, Lorie Leo, Alejandro Raimondi, Jeffery D. Molkentin, Steven R. Lentz, and Jorge Di Paola Blood 2008 111: 1257-1265. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bozza, F. A. Articles by Weyrich, A. S. Search for Related Content PubMed Articles by Bozza, F. A. Articles by Weyrich, A. S. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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