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Mitofusin-2 Regulates Platelet Mitochondria and Function.
Jacob, Shancy; Kosaka, Yasuhiro; Bhatlekar, Seema; Denorme, Frederik; Benzon, Haley; Moody, Alexandra; Moody, Victoria; Tugolukova, Emilia A; Hull, Grayson; Kishimoto, Nina; Manne, Bhanu K; Guo, Li; Souvenir, Rhonda; Seliger, Brayden J; Eustes, Alicia S; Hoerger, Kelly; Tolley, Neal D; Fatahian, Amir N; Boudina, Sihem; Christiani, David C; Wei, Yongyue; Ju, Can; Campbell, Robert A; Rondina, Matthew T; Abel, E Dale; Bray, Paul F; Weyrich, Andrew S; Rowley, Jesse W.
Afiliación
  • Jacob S; Molecular Medicine Program, (S.J., Y.K., S. Bhatlekar, F.D., H.B., A.M., V.M., E.T., G.H., N.K., B.K.M., B.J.S., K.H., N.D.T., S. Boudina, R.A.C., M.T.R., P.F.B., A.S.W., J.W.R.), University of Utah, Salt Lake City, UT.
  • Kosaka Y; Molecular Medicine Program, (S.J., Y.K., S. Bhatlekar, F.D., H.B., A.M., V.M., E.T., G.H., N.K., B.K.M., B.J.S., K.H., N.D.T., S. Boudina, R.A.C., M.T.R., P.F.B., A.S.W., J.W.R.), University of Utah, Salt Lake City, UT.
  • Bhatlekar S; Molecular Medicine Program, (S.J., Y.K., S. Bhatlekar, F.D., H.B., A.M., V.M., E.T., G.H., N.K., B.K.M., B.J.S., K.H., N.D.T., S. Boudina, R.A.C., M.T.R., P.F.B., A.S.W., J.W.R.), University of Utah, Salt Lake City, UT.
  • Denorme F; Molecular Medicine Program, (S.J., Y.K., S. Bhatlekar, F.D., H.B., A.M., V.M., E.T., G.H., N.K., B.K.M., B.J.S., K.H., N.D.T., S. Boudina, R.A.C., M.T.R., P.F.B., A.S.W., J.W.R.), University of Utah, Salt Lake City, UT.
  • Benzon H; Molecular Medicine Program, (S.J., Y.K., S. Bhatlekar, F.D., H.B., A.M., V.M., E.T., G.H., N.K., B.K.M., B.J.S., K.H., N.D.T., S. Boudina, R.A.C., M.T.R., P.F.B., A.S.W., J.W.R.), University of Utah, Salt Lake City, UT.
  • Moody A; Molecular Medicine Program, (S.J., Y.K., S. Bhatlekar, F.D., H.B., A.M., V.M., E.T., G.H., N.K., B.K.M., B.J.S., K.H., N.D.T., S. Boudina, R.A.C., M.T.R., P.F.B., A.S.W., J.W.R.), University of Utah, Salt Lake City, UT.
  • Moody V; Molecular Medicine Program, (S.J., Y.K., S. Bhatlekar, F.D., H.B., A.M., V.M., E.T., G.H., N.K., B.K.M., B.J.S., K.H., N.D.T., S. Boudina, R.A.C., M.T.R., P.F.B., A.S.W., J.W.R.), University of Utah, Salt Lake City, UT.
  • Tugolukova EA; Molecular Medicine Program, (S.J., Y.K., S. Bhatlekar, F.D., H.B., A.M., V.M., E.T., G.H., N.K., B.K.M., B.J.S., K.H., N.D.T., S. Boudina, R.A.C., M.T.R., P.F.B., A.S.W., J.W.R.), University of Utah, Salt Lake City, UT.
  • Hull G; Molecular Medicine Program, (S.J., Y.K., S. Bhatlekar, F.D., H.B., A.M., V.M., E.T., G.H., N.K., B.K.M., B.J.S., K.H., N.D.T., S. Boudina, R.A.C., M.T.R., P.F.B., A.S.W., J.W.R.), University of Utah, Salt Lake City, UT.
  • Kishimoto N; Molecular Medicine Program, (S.J., Y.K., S. Bhatlekar, F.D., H.B., A.M., V.M., E.T., G.H., N.K., B.K.M., B.J.S., K.H., N.D.T., S. Boudina, R.A.C., M.T.R., P.F.B., A.S.W., J.W.R.), University of Utah, Salt Lake City, UT.
  • Manne BK; Molecular Medicine Program, (S.J., Y.K., S. Bhatlekar, F.D., H.B., A.M., V.M., E.T., G.H., N.K., B.K.M., B.J.S., K.H., N.D.T., S. Boudina, R.A.C., M.T.R., P.F.B., A.S.W., J.W.R.), University of Utah, Salt Lake City, UT.
  • Guo L; Division of Hematology and Oncology, Bloodworks Northwest Research Institute, Seattle, WA (L.G.).
  • Souvenir R; David Geffen School of Medicine and UCLA Health (R.S., E.D.A.), Los Angeles, CA.
  • Seliger BJ; Molecular Medicine Program, (S.J., Y.K., S. Bhatlekar, F.D., H.B., A.M., V.M., E.T., G.H., N.K., B.K.M., B.J.S., K.H., N.D.T., S. Boudina, R.A.C., M.T.R., P.F.B., A.S.W., J.W.R.), University of Utah, Salt Lake City, UT.
  • Eustes AS; University of Iowa (A.S.E.), Iowa City, IA.
  • Hoerger K; Molecular Medicine Program, (S.J., Y.K., S. Bhatlekar, F.D., H.B., A.M., V.M., E.T., G.H., N.K., B.K.M., B.J.S., K.H., N.D.T., S. Boudina, R.A.C., M.T.R., P.F.B., A.S.W., J.W.R.), University of Utah, Salt Lake City, UT.
  • Tolley ND; Molecular Medicine Program, (S.J., Y.K., S. Bhatlekar, F.D., H.B., A.M., V.M., E.T., G.H., N.K., B.K.M., B.J.S., K.H., N.D.T., S. Boudina, R.A.C., M.T.R., P.F.B., A.S.W., J.W.R.), University of Utah, Salt Lake City, UT.
  • Fatahian AN; Department of Nutrition and Integrative Physiology (A.N.F., S. Boudina), University of Utah, Salt Lake City, UT.
  • Boudina S; Molecular Medicine Program, (S.J., Y.K., S. Bhatlekar, F.D., H.B., A.M., V.M., E.T., G.H., N.K., B.K.M., B.J.S., K.H., N.D.T., S. Boudina, R.A.C., M.T.R., P.F.B., A.S.W., J.W.R.), University of Utah, Salt Lake City, UT.
  • Christiani DC; Department of Nutrition and Integrative Physiology (A.N.F., S. Boudina), University of Utah, Salt Lake City, UT.
  • Wei Y; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA (D.C.C.).
  • Ju C; Department of Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, MA (D.C.C.).
  • Campbell RA; Peking University Center for Public Health and Epidemic Preparedness and Response, Beijing, China (Y.W.).
  • Rondina MT; Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China (Y.W.).
  • Abel ED; Department of Biostatistics, School of Public Health, Nanjing Medical University, Jiangsu, China (C.J.).
  • Bray PF; Molecular Medicine Program, (S.J., Y.K., S. Bhatlekar, F.D., H.B., A.M., V.M., E.T., G.H., N.K., B.K.M., B.J.S., K.H., N.D.T., S. Boudina, R.A.C., M.T.R., P.F.B., A.S.W., J.W.R.), University of Utah, Salt Lake City, UT.
  • Weyrich AS; Division of Hematology and Hematologic Malignancies (R.A.C., M.T.R., P.F.B), University of Utah, Salt Lake City, UT.
  • Rowley JW; Department of Internal Medicine (P.F.B., J.W.R, M.T.R., R.A.C.), University of Utah, Salt Lake City, UT.
Circ Res ; 134(2): 143-161, 2024 01 19.
Article en En | MEDLINE | ID: mdl-38156445
ABSTRACT

BACKGROUND:

Single-nucleotide polymorphisms linked with the rs1474868 T allele (MFN2 [mitofusin-2] T/T) in the human mitochondrial fusion protein MFN2 gene are associated with reduced platelet MFN2 RNA expression and platelet counts. This study investigates the impact of MFN2 on megakaryocyte and platelet biology.

METHODS:

Mice with megakaryocyte/platelet deletion of Mfn2 (Mfn2-/- [Mfn2 conditional knockout]) were generated using Pf4-Cre crossed with floxed Mfn2 mice. Human megakaryocytes were generated from cord blood and platelets isolated from healthy subjects genotyped for rs1474868. Ex vivo approaches assessed mitochondrial morphology, function, and platelet activation responses. In vivo measurements included endogenous/transfused platelet life span, tail bleed time, transient middle cerebral artery occlusion, and pulmonary vascular permeability/hemorrhage following lipopolysaccharide-induced acute lung injury.

RESULTS:

Mitochondria was more fragmented in megakaryocytes derived from Mfn2-/- mice and from human cord blood with MFN2 T/T genotype compared with control megakaryocytes. Human resting platelets of MFN2 T/T genotype had reduced MFN2 protein, diminished mitochondrial membrane potential, and an increased rate of phosphatidylserine exposure during ex vivo culture. Platelet counts and platelet life span were reduced in Mfn2-/- mice accompanied by an increased rate of phosphatidylserine exposure in resting platelets, especially aged platelets, during ex vivo culture. Mfn2-/- also decreased platelet mitochondrial membrane potential (basal) and activated mitochondrial oxygen consumption rate, reactive oxygen species generation, calcium flux, platelet-neutrophil aggregate formation, and phosphatidylserine exposure following dual agonist activation. Ultimately, Mfn2-/- mice showed prolonged tail bleed times, decreased ischemic stroke infarct size after cerebral ischemia-reperfusion, and exacerbated pulmonary inflammatory hemorrhage following lipopolysaccharide-induced acute lung injury. Analysis of MFN2 SNPs in the iSPAAR study (Identification of SNPs Predisposing to Altered ALI Risk) identified a significant association between MFN2 and 28-day mortality in patients with acute respiratory distress syndrome.

CONCLUSIONS:

Mfn2 preserves mitochondrial phenotypes in megakaryocytes and platelets and influences platelet life span, function, and outcomes of stroke and lung injury.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Lipopolisacáridos / Lesión Pulmonar Aguda Límite: Aged / Animals / Humans Idioma: En Revista: Circ Res Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Lipopolisacáridos / Lesión Pulmonar Aguda Límite: Aged / Animals / Humans Idioma: En Revista: Circ Res Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos