ReviewPoly(ADP-ribose) signals to mitochondrial AIF: A key event in parthanatos
Introduction
Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein contributing to both cell life and death (Boujrad et al., 2007, Krantic et al., 2007, Modjtahedi et al., 2006). Under physiological conditions, AIF maintains mitochondrial structure (Cheung et al., 2006) and plays an essential role in oxidative phosphorylation (Joza et al., 2005, Vahsen et al., 2004). Conversely, under pathological conditions, AIF is a key mediator of caspase-independent cell death. Although the mechanism of how AIF contributes to cell death is obscure, one pivotal event is that mitochondrial AIF translocates to nucleus, where it induces chromatin condensation and large-scale DNA fragmentation (≈ 50 kb) leading to cell death (Susin et al., 1999).
AIF is a key factor that mediates poly(ADP-ribose) polymerase-1 (PARP-1)-dependent cell death (Yu et al., 2002). PARP-1-mediated cell death differs from other forms of cell death, such as apoptosis, necrosis and autophagy (Table 1). It causes phosphatidylserine flipping onto the outer plasma membrane, dissipation of mitochondrial membrane potential, chromatin condensation and large DNA fragmentation (Delettre et al., 2006a, Delettre et al., 2006b, Susin et al., 1999, Wang et al., 2004, Yu et al., 2002). However, unlike apoptosis, it does not cause apoptotic body formation or small scale DNA fragmentation. Moreover, PARP-1-induced cell death cannot be rescued by pan-caspase inhibitors, such as z-VAD-fmk and boc-aspartyl-fmk (BAF) (Yu et al., 2002). Although PARP-1-mediated cell death shows loss of membrane integrity similar to necrosis, it does not induce cell swelling (Wang et al., 2004, Yu et al., 2002). It also clearly differs from autophagy, which involves autophagic vacuoles formation and lysosomal degradation (Edinger and Thompson, 2004, Kroemer et al., 2005). These observations suggest that PARP-1-mediated cell death is unique compared with apoptosis, necrosis and autophagy. To distinguish from other forms of cell death, PARP-1-mediated cell death is named as parthanatos, after poly(ADP-ribose) (PAR) polymer, which is a product of PARP-1 activation and thanatos, which is the Greek personification of death and mortality (Harraz et al., 2008).
The roles of AIF and parthanatos have been widely implicated in some neurologic diseases. Recently, new progress has been made to elucidate the mechanism of mitochondrial AIF release in different forms of cell death. Our group found that nonprotein PAR polymer functions as a cell death signal and plays a pivotal role in mitochondrial AIF release in parthanatos (Andrabi et al., 2006, Yu et al., 2006). Here, we review biological properties and functions of AIF in neurologic diseases and the mechanism of mitochondrial AIF release.
Section snippets
AIF properties and mitochondrial location
AIF, which was initially identified from mouse liver mitochondria following permeability transition pore opening, comprises 16 exons and is located on chromosome X (Susin et al., 1999). It is synthesized as a 67 kDa-precursor in the cytoplasm and imported into mitochondria. It contains a predicted mitochondrial localization sequence (MLS) in its N-terminus (Fig. 1). During mitochondria import, AIF is processed to the mature 62 kDa form by cleavage at Met54/Ala55 (Fig. 1B) (Otera et al., 2005).
AIF and cell death/survival
AIF is a bifunctional flavoprotein with a vital function in bioenergetics within mitochondria and a lethal function in cell death when it moves to the nucleus. During cortical development, AIF is required for neuronal cell survival (Cheung et al., 2006). It is involved in normal mitochondrial respiration in neurons possibly by stabilizing mitochondrial complex I (Joza et al., 2005) or maintaining mitochondrial structure (Cheung et al., 2006). Loss of AIF in muscle leads to mitochondrial
AIF, parthanatos and neurologic diseases
As a caspase-independent cell death effector, AIF plays an important role in ischemia and stroke. Stroke is the third cause of death and disability in the United States, just behind diseases of the heart and cancer (Koh et al., 2005a, Koh et al., 2005b). Neuronal damage and cell death following stroke and ischemia is a primary cause of subsequent morbidity and mortality (Koh et al., 2005a, Koh et al., 2005b). Over the past decade, a large body of evidence demonstrates that activation of PARP-1
Therapeutic targets
PARP-1 activation, PAR polymer formation, mitochondrial AIF release and nuclear translocation, AIF-mediated chromatin condensation/DNA fragmentation are four key steps in parthanatos (Fig. 3), which has been implicated to play a pivotal role in multiple neurologic diseases. Therefore, PARP-1, PAR polymer and AIF could be potential targets for therapy of neurologic disorders.
PARP inhibitors can block PARP-1 activation, thereby regulating PAR levels. Several inhibitors, like 1,
Concluding remarks
Excessive activation of PARP-1 leads to cell death through a mechanism designated parthanatos. The molecular mechanism for parthanatos involves the release of AIF from mitochondria and translocation to the nucleus. PAR polymer generated by PARP-1 activation plays a pivotal role in this deadly crosstalk between the nucleus and mitochondria. PAR polymer itself functions as a cell death signal that translocates from nucleus to mitochondria to mediate AIF release from mitochondria. The exact
Acknowledgments
This work was supported by grants from the NIH (NS39148), the American Heart Association Postdoctoral Fellowship Award to YW. T.M.D. is the Leonard and Madlyn Abramson Professor of Neurodegenerative Disease at Johns Hopkins University.
References (91)
- et al.
Alteration of poly(ADP-ribose) glycohydrolase nucleocytoplasmic shuttling characteristics upon cleavage by apoptotic proteases
Biol. Cell.
(2003) Poly(ADP-ribosyl)ation and stroke
Pharmacol. Res.
(2005)- et al.
Determination of peptide substrate specificity for mu-calpain by a peptide library-based approach: the importance of primed side interactions
J. Biol. Chem.
(2005) - et al.
Importance of poly(ADP-ribose) glycohydrolase in the control of poly(ADP-ribose) metabolism
Exp. Cell. Res.
(2001) - et al.
AIFsh, a novel apoptosis-inducing factor (AIF) pro-apoptotic isoform with potential pathological relevance in human cancer
J. Biol. Chem.
(2006) - et al.
Identification and characterization of AIFsh2, a mitochondrial apoptosis-inducing factor (AIF) isoform with NADH oxidase activity
J. Biol. Chem.
(2006) - et al.
Death by design: apoptosis, necrosis and autophagy
Curr. Opin. Cell. Biol.
(2004) - et al.
Neither energy collapse nor transcription underlie in vitro neurotoxicity of poly(ADP-ribose) polymerase hyper-activation
Neurochem. Int.
(2007) - et al.
Mitochondrial localization of mu-calpain
Biochem. Biophys. Res. Commun.
(2005) - et al.
Niacin, poly(ADP-ribose) polymerase-1 and genomic stability
Mutat. Res.
(2001)
Dynamic relocation of poly(ADP-ribose) glycohydrolase isoforms during radiation-induced DNA damage
Biochim. Biophys. Acta.
Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling
Trends Pharmacol. Sci.
Association of the calpain/calpastatin network with subcellular organelles
Biochem. Biophys. Res. Commun.
Poly(ADP-Ribose) synthetase. Separation and identification of three proteolytic fragments as the substrate-binding domain, the DNA-binding domain, and the automodification domain
J. Biol. Chem.
Mediation of cell death by poly(ADP-ribose) polymerase-1
Pharmacol. Res.
Apoptosis-inducing factor: a matter of neuron life and death
Prog. Neurobiol.
Isolation and characterization of the cDNA encoding bovine poly(ADP-ribose) glycohydrolase
J. Biol. Chem.
Therapeutic potential of AIF-mediated caspase-independent programmed cell death
Drug Resist. Updat.
Two small enzyme isoforms mediate mammalian mitochondrial poly(ADP-ribose) glycohydrolase (PARG) activity
Exp. Cell Res.
Human poly(ADP-ribose) glycohydrolase is expressed in alternative splice variants yielding isoforms that localize to different cell compartments
Exp. Cell. Res.
NADH oxidase activity of mitochondrial apoptosis-inducing factor
J. Biol. Chem.
Apoptosis-inducing factor: vital and lethal
Trends Cell. Biol.
Poly(ADP-ribose) polymerase, nitric oxide and cell death
Trends Pharmacol. Sci.
Calpain I induces cleavage and release of apoptosis-inducing factor from isolated mitochondria
J. Biol. Chem.
Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes
Cell
Distinct hsp70 domains mediate apoptosis-inducing factor release and nuclear accumulation
J. Biol. Chem.
Roles of poly(ADP-ribosyl)ation and PARP in apoptosis, DNA repair, genomic stability and functions of p53 and E2F-1
Adv. Enzyme Regul.
Poly(ADP-ribose) glycohydrolase is present and active in mammalian cells as a 110-kDa protein
Exp. Cell. Res.
Poly(ADP-ribose) polymerase-1 signaling to mitochondria in necrotic cell death requires RIP1/TRAF2-mediated JNK1 activation
J. Biol. Chem.
Assignment of the poly(ADP-ribose) glycohydrolase gene (PARG) to human chromosome 10q11.23 and mouse chromosome 14B by in situ hybridization
Cytogenet. Cell Genet.
Poly(ADP-ribose) (PAR) polymer is a death signal
Proc. Natl. Acad. Sci. U. S. A.
Mitochondrial release of apoptosis-inducing factor occurs downstream of cytochrome c release in response to several proapoptotic stimuli
J. Cell. Biol.
Mechanistic role of calpains in postischemic neurodegeneration
J. Cereb. Blood Flow Metab.
Poly(ADP-ribose) glycohydrolase silencing protects against H2O2-induced cell death
Biochem. J.
Regulation of poly(ADP-ribose) metabolism by poly(ADP-ribose) glycohydrolase: where and when?
Cell. Mol. Life. Sci.
AIF-mediated programmed necrosis: a highly regulated way to die
Cell. Cycle
Critical role of calpain I in mitochondrial release of apoptosis-inducing factor in ischemic neuronal injury
J. Neurosci.
Apoptosis-inducing factor is a key factor in neuronal cell death propagated by BAX-dependent and BAX-independent mechanisms
J. Neurosci.
Dissociating the dual roles of apoptosis-inducing factor in maintaining mitochondrial structure and apoptosis
EMBO J.
Inhibitors of poly(ADP-ribose) polymerase-1 suppress transcriptional activation in lymphocytes and ameliorate autoimmune encephalomyelitis in rats
Br. J. Pharmacol.
Depletion of the 110-kilodalton isoform of poly(ADP-ribose) glycohydrolase increases sensitivity to genotoxic and endotoxic stress in mice
Mol. Cell. Biol.
Implication of poly(ADP-ribose) polymerase (PARP) in neurodegeneration and brain energy metabolism. Decreases in mouse brain NAD+ and ATP caused by MPTP are prevented by the PARP inhibitor benzamide
Ann. N. Y. Acad. Sci.
Apoptosis-inducing factor is involved in the regulation of caspase-independent neuronal cell death
J. Cell. Biol.
Apoptosis-inducing factor triggered by poly(ADP-ribose) polymerase and Bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia
J. Neurosci.
Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions
Biochem. J.
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