AIM: Reactive oxygen species (ROS) plays important roles in aging. However, the specific mechanisms for intracellular ROS accumulation, especially during aging, remain elusive. RESULTS: We have reported that Fas-associated protein with death domain (FADD) phosphorylation abolishes the recruitment of phosphatase type 2A C subunit (PP2Ac) to protein kinase C (PKC)βII, which specifically regulates mitochondrial ROS generation by p66shc. Here, we have studied the role of FADD phosphorylation in an FADD constitutive-phosphorylation mutation (FADD-D) mouse model. In FADD-D mice, the constitutive FADD phosphorylation led to ROS accumulation (hydrogen peroxide [H₂O₂]), in a process that was dependent on PKCβ and accompanied by increased PKCβ and p66shc phosphorylation, impaired mitochondrial integrity, and enhanced sensitivity to oxidative stress-mediated apoptosis. Moreover, FADD-D mice exhibited premature aging-like phenotypes, including DNA damage, cellular senescence, and shortened lifespan. In addition, we demonstrate that FADD phosphorylation and the recruitment of PP2A and FADD to PKCβ are induced responses to oxidative stress, and that the extent of FADD phosphorylation in wild-type mice was augmented during aging, accompanied by impairment of the interaction between PKCβ and PP2A. INNOVATION: The present study first addresses the role of FADD phosphorylation in aging through controlling mitochondrial ROS specifically generated by PKCβ. CONCLUSION: These data identify that FADD phosphorylation is critical for the PKCβ-p66shc signaling route to generate H₂O₂ and to implicate enhanced FADD phosphorylation as a primary cause of ROS accumulation during aging.
AIM: Reactive oxygen species (ROS) plays important roles in aging. However, the specific mechanisms for intracellular ROS accumulation, especially during aging, remain elusive. RESULTS: We have reported that Fas-associated protein with death domain (FADD) phosphorylation abolishes the recruitment of phosphatase type 2A C subunit (PP2Ac) to protein kinase C (PKC)βII, which specifically regulates mitochondrial ROS generation by p66shc. Here, we have studied the role of FADD phosphorylation in an FADD constitutive-phosphorylation mutation (FADD-D) mouse model. In FADD-D mice, the constitutive FADD phosphorylation led to ROS accumulation (hydrogen peroxide [H₂O₂]), in a process that was dependent on PKCβ and accompanied by increased PKCβ and p66shc phosphorylation, impaired mitochondrial integrity, and enhanced sensitivity to oxidative stress-mediated apoptosis. Moreover, FADD-D mice exhibited premature aging-like phenotypes, including DNA damage, cellular senescence, and shortened lifespan. In addition, we demonstrate that FADD phosphorylation and the recruitment of PP2A and FADD to PKCβ are induced responses to oxidative stress, and that the extent of FADD phosphorylation in wild-type mice was augmented during aging, accompanied by impairment of the interaction between PKCβ and PP2A. INNOVATION: The present study first addresses the role of FADD phosphorylation in aging through controlling mitochondrial ROS specifically generated by PKCβ. CONCLUSION: These data identify that FADD phosphorylation is critical for the PKCβ-p66shc signaling route to generate H₂O₂ and to implicate enhanced FADD phosphorylation as a primary cause of ROS accumulation during aging.
Authors: Jan de Boer; Jaan Olle Andressoo; Jan de Wit; Jan Huijmans; Rudolph B Beems; Harry van Steeg; Geert Weeda; Gijsbertus T J van der Horst; Wibeke van Leeuwen; Axel P N Themmen; Morteza Meradji; Jan H J Hoeijmakers Journal: Science Date: 2002-04-11 Impact factor: 47.728
Authors: E Migliaccio; M Giorgio; S Mele; G Pelicci; P Reboldi; P P Pandolfi; L Lanfrancone; P G Pelicci Journal: Nature Date: 1999-11-18 Impact factor: 49.962
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Authors: Balaraman Kalyanaraman; Victor Darley-Usmar; Kelvin J A Davies; Phyllis A Dennery; Henry Jay Forman; Matthew B Grisham; Giovanni E Mann; Kevin Moore; L Jackson Roberts; Harry Ischiropoulos Journal: Free Radic Biol Med Date: 2011-10-02 Impact factor: 7.376
Authors: Carola A Neumann; Daniela S Krause; Christopher V Carman; Shampa Das; Devendra P Dubey; Jennifer L Abraham; Roderick T Bronson; Yuko Fujiwara; Stuart H Orkin; Richard A Van Etten Journal: Nature Date: 2003-07-31 Impact factor: 49.962
Authors: Alfredo Ramos-Miguel; Jesús A García-Sevilla; Alasdair M Barr; Thomas A Bayer; Peter Falkai; Sue E Leurgans; Julie A Schneider; David A Bennett; William G Honer; M Julia García-Fuster Journal: Mol Neurodegener Date: 2017-03-20 Impact factor: 14.195