Elsevier

Experimental Neurology

Volume 218, Issue 2, August 2009, Pages 193-202
Experimental Neurology

Review
Poly(ADP-ribose) signals to mitochondrial AIF: A key event in parthanatos

https://doi.org/10.1016/j.expneurol.2009.03.020Get rights and content

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) plays a pivotal role in multiple neurologic diseases by mediating caspase-independent cell death, which has recently been designated parthanatos to distinguish it from other forms of cell death such as apoptosis, necrosis and autophagy. Mitochondrial apoptosis-inducing factor (AIF) release and translocation to the nucleus is the commitment point for parthanatos. This process involves a pathogenic role of poly(ADP-ribose) (PAR) polymer. It generates in the nucleus and translocates to the mitochondria to mediate AIF release following lethal PARP-1 activation. PAR polymer itself is toxic to cells. Thus, PAR polymer signaling to mitochondrial AIF is the key event initiating the deadly crosstalk between the nucleus and the mitochondria in parthanatos. Targeting PAR-mediated AIF release could be a potential approach for the therapy of neurologic disorders.

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.

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