title: Deadly conversations: nuclear-mitochondrial cross-talk.
abstract: Neuronal damage following stroke or neurodegenerative diseases is thought to stem in part from overexcitation of N -methyl-D-aspartate (NMDA) receptors by glutamate. NMDA receptors triggered neurotoxicity is mediated in large part by activation of neuronal nitric oxide synthase (nNOS) and production of nitric oxide (NO). Simultaneous production of superoxide anion in mitochondria provides a permissive environment for the formation of peroxynitrite (ONOO-). Peroxynitrite damages DNA leading to strand breaks and activation of poly(ADP-ribose) polymerase-1 (PARP-1). This signal cascade plays a key role in NMDA excitotoxicity, and experimental models of stroke and Parkinson's disease. The mechanisms of PARP-1-mediated neuronal death are just being revealed. While decrements in ATP and NAD are readily observed following PARP activation, it is not yet clear whether loss of ATP and NAD contribute to the neuronal death cascade or are simply a biochemical marker for PARP-1 activation. Apoptosis-inducing factor (AIF) is normally localized to mitochondria but following PARP-1 activation, AIF translocates to the nucleus triggering chromatin condensation, DNA fragmentation and nuclear shrinkage. Additionally, phosphatidylserine is exposed and at a later time point cytochrome c is released and caspase-3 is activated. In the setting of excitotoxic neuronal death, AIF toxicity is caspase independent. These observations are consistent with reports of biochemical features of apoptosis in neuronal injury models but modest to no protection by caspase inhibitors. It is likely that AIF is the effector of the morphologic and biochemical events and is the commitment point to neuronal cell death, events that occur prior to caspase activation, thus accounting for the limited effects of caspase inhibitors. There exists significant cross talk between the nucleus and mitochondria, ultimately resulting in neuronal cell death. In exploiting this pathway for the development of new therapeutics, it will be important to block AIF translocation from the mitochondria to the nucleus without impairing important physiological functions of AIF in the mitochondria.
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. vdawson@jhmi.edu
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor; D002467:Cell Nucleus / Q000378:metabolism*; D005420:Flavoproteins / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D005420:Flavoproteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D011065:Poly(ADP-ribose) Polymerases