A critical role of fas-associated protein with death domain phosphorylation in intracellular reactive oxygen species homeostasis and 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 [H₂O ₂]), 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. Antioxid. Redox Signal. 21, 33-45.