title: Requirement of FADD, NEMO, and BAX/BAK for aberrant mitochondrial function in tumor necrosis factor alpha-induced necrosis.
abstract: Necroptosis represents a form of alternative programmed cell death that is dependent on the kinase RIP1. RIP1-dependent necroptotic death manifests as increased reactive oxygen species (ROS) production in mitochondria and is accompanied by loss of ATP biogenesis and eventual dissipation of mitochondrial membrane potential. Here, we show that tumor necrosis factor alpha (TNF-α)-induced necroptosis requires the adaptor proteins FADD and NEMO. FADD was found to mediate formation of the TNF-α-induced pronecrotic RIP1-RIP3 kinase complex, whereas the IκB Kinase (IKK) subunit NEMO appears to function downstream of RIP1-RIP3. Interestingly, loss of RelA potentiated TNF-α-dependent necroptosis, indicating that NEMO regulates necroptosis independently of NF-κB. Using both pharmacologic and genetic approaches, we demonstrate that the overexpression of antioxidants alleviates ROS elevation and necroptosis. Finally, elimination of BAX and BAK or overexpression of Bcl-x(L) protects cells from necroptosis at a later step. These findings provide evidence that mitochondria play an amplifying role in inflammation-induced necroptosis.
authors: Department of Biochemistry, Temple University, Philadelphia, PA 19140, USA.
authors: Krishna M
authors: KM
authors: Irrinki
authors: Karthik
authors: K
authors: Mallilankaraman
authors: Roshan J
authors: RJ
authors: Thapa
authors: Harish C
authors: HC
authors: Chandramoorthy
authors: Frank J
authors: FJ
authors: Smith
authors: Neelakshi R
authors: NR
authors: Jog
authors: Rajesh Kumar
authors: RK
authors: Gandhirajan
authors: Steven G
authors: SG
authors: Kelsen
authors: Steven R
authors: SR
authors: Houser
authors: Michael J
authors: MJ
authors: May
authors: Siddharth
authors: S
authors: Balachandran
authors: Muniswamy
authors: M
authors: Madesh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D005434:Flow Cytometry; D020690:GTPase-Activating Proteins / Q000378:metabolism; D055786:Gene Knockout Techniques; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis / Q000378:metabolism*; D017382:Reactive Oxygen Species; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000172:deficiency / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000378:metabolism*
chemical_list: C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D020690:GTPase-Activating Proteins; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; C490620:Ralbp1 protein, mouse; D017382:Reactive Oxygen Species; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse