title: A critical role of Fas-associated protein with death domain phosphorylation in intracellular reactive oxygen species homeostasis and aging.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  The present study first addresses the role of FADD phosphorylation in aging through controlling mitochondrial ROS specifically generated by PKCβ.
  
  
  CONCLUSIONS
  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.affiliation: 1 State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, School of Stomatology, Affiliated Stomatological Hospital, Nanjing University , Nanjing, People's Republic of China .
authors.forename: Wei
authors.initials: W
authors.lastname: Cheng
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.forename: Chun
authors.initials: C
authors.lastname: Yao
authors.forename: Liangqiang
authors.initials: L
authors.lastname: He
authors.forename: Kunzhi
authors.initials: K
authors.lastname: Jia
authors.forename: Bingya
authors.initials: B
authors.lastname: Yang
authors.forename: Pan
authors.initials: P
authors.lastname: Du
authors.forename: Hongqin
authors.initials: H
authors.lastname: Zhuang
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Chen
authors.forename: Zexu
authors.initials: Z
authors.lastname: Liu
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ding
authors.forename: Zichun
authors.initials: Z
authors.lastname: Hua
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D053200:Fas-Associated Death Domain Protein; D017382:Reactive Oxygen Species