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Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death 总被引:1,自引:0,他引:1
Baines CP Kaiser RA Purcell NH Blair NS Osinska H Hambleton MA Brunskill EW Sayen MR Gottlieb RA Dorn GW Robbins J Molkentin JD 《Nature》2005,434(7033):658-662
Mitochondria play a critical role in mediating both apoptotic and necrotic cell death. The mitochondrial permeability transition (mPT) leads to mitochondrial swelling, outer membrane rupture and the release of apoptotic mediators. The mPT pore is thought to consist of the adenine nucleotide translocator, a voltage-dependent anion channel, and cyclophilin D (the Ppif gene product), a prolyl isomerase located within the mitochondrial matrix. Here we generated mice lacking Ppif and mice overexpressing cyclophilin D in the heart. Ppif null mice are protected from ischaemia/reperfusion-induced cell death in vivo, whereas cyclophilin D-overexpressing mice show mitochondrial swelling and spontaneous cell death. Mitochondria isolated from the livers, hearts and brains of Ppif null mice are resistant to mitochondrial swelling and permeability transition in vitro. Moreover, primary hepatocytes and fibroblasts isolated from Ppif null mice are largely protected from Ca2+-overload and oxidative stress-induced cell death. However, Bcl-2 family member-induced cell death does not depend on cyclophilin D, and Ppif null fibroblasts are not protected from staurosporine or tumour-necrosis factor-alpha-induced death. Thus, cyclophilin D and the mitochondrial permeability transition are required for mediating Ca2+- and oxidative damage-induced cell death, but not Bcl-2 family member-regulated death. 相似文献
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Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation 总被引:20,自引:0,他引:20
Wong KK Chang S Weiler SR Ganesan S Chaudhuri J Zhu C Artandi SE Rudolph KL Gottlieb GJ Chin L Alt FW DePinho RA 《Nature genetics》2000,26(1):85-88
Telomeres are specialized nucleoprotein complexes that serve as protective caps of linear eukaryotic chromosomes. Loss of telomere function is associated with rampant genetic instability and loss of cellular viability and renewal potential. The telomere also participates in processes of chromosomal repair, as evidenced by the 'capture' or de novo synthesis of telomere repeats at double-stranded breaks and by the capacity of yeast telomeres to serve as repositories of essential components of the DNA repair machinery, particularly those involved in non-homologous end-joining (NHEJ). Here we used the telomerase-deficient mouse, null for the essential telomerase RNA gene (Terc), to assess the role of telomerase and telomere function on the cellular and organismal response to ionizing radiation. Although the loss of telomerase activity per se had no discernable impact on the response to ionizing radiation, the emergence of telomere dysfunction in late-generation Terc-/- mice imparted a radiosensitivity syndrome associated with accelerated mortality. On the cellular level, the gastrointestinal crypt stem cells and primary thymocytes showed increased rates of apoptosis, and mouse embryonic fibroblasts (MEFs) showed diminished dose-dependent clonogenic survival. The radiosensitivity of telomere dysfunctional cells correlated with delayed DNA break repair kinetics, persistent chromosomal breaks and cytogenetic profiles characterized by complex chromosomal aberrations and massive fragmentation. Our findings establish a intimate relationship between functionally intact telomeres and the genomic, cellular and organismal response to ionizing radiation. 相似文献
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F. J. Gottlieb R. Goitein L. Ehrman S. McAvoy 《Cellular and molecular life sciences : CMLS》1977,33(11):1436
Summary A successful attempt was made to culture the mycoplasmalike microorganism causing semispecific hybrid male sterility inDrosophila paulistorum utilizingEphestia kühniella as the intermediate host. Data gleaned from this passage indicates that the induction of sterility depends upon the quality not the quantity of infectious intracellular symbionts. 相似文献
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J. B. Weissberg F. A. Oski M.D. A. J. Gottlieb 《Cellular and molecular life sciences : CMLS》1970,26(10):1062-1063
Zusammenfassung In Erythrozyten ist die Synthese von 2, 3-Diphosphoglycerat aus Fructose-1, 6-diphosphat in anaerobem Milieu um 18% höher als unter aeroben-Bedingungen. Das anaerobe Milieu steigert die Aktivität der Glyceraldehyd-3-phosphat-dehydrogenase um 300%. 相似文献
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