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

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.

Figure 1

A. Structure of five different human AIF isoforms. Full-length AIF is encoded by a 16-exon X chromosome gene giving rise to a protein precursor composed of 613 amino acids (Susin, et al., 1999). AIF-exB is an isoform with 609 amino acids generated by the alternative usage of exon 2b instead of exon 2 (Loeffler, et al., 2001). AIF and AIF-exB both contain three functional domains: FAD-binding domains D1 (black), NADH-binding domain D2 (white) and C-terminal domain D3 (gray), and a mitochondrial localization sequence (MLS) at the N-terminus and a nuclear localization sequence (NLS) at the C-terminus. Short AIF (AIFsh) contains C-terminal AIF encoded by exons 10–16, lacking of MLS. AIFsh2 and AIFsh3 are generated by the alternative splicing of the exon 9b (Delettre, et al., 2006). AIFsh2 contains the MLS and the oxidoreductase domain, but lacks the C-terminus of AIF. AIFsh3 has a similar structure as AIFsh2 with the splicing of exon 2, which leads to the loss of MLS. B. Graphic representation of precursor AIF, mature AIF and truncated AIF.

Figure 2. Regulation of PAR polymer generation and degradation

Severe DNA damage causes excessive activation of PARPs, especially PARP-1. PARPs use nicotinamide adenine dinucleotide (NAD⁺) as substrate to generate PAR polymer and nicotinamide (Nam) (step 1). Numerous nuclear proteins are acceptors of PAR polymer. PARPs catalyze the addition of PAR onto itself and other acceptor proteins, resulting in poly(ADP-ribosyl)ation. This modification might affect the functions of acceptor proteins (step 2). PARG can quickly catalyze the hydrolysis of PAR polymer into free ADP-ribose (step 3).

Figure 3. Schematic model of PARP-1-, PAR polymer- and AIF-mediated death signal in parthanatos

PARP-1 activation, PAR polymer formation, mitochondrial AIF release, AIF-mediated chromatin condensation and DNA fragmentation are four key steps in parthanatos. Step 1, DNA damage by NMDA or MNNG administration activates PARP-1. Excitotoxic activation of NMDA receptor can induce calcium influx, nNOS activation, NO production and reactive oxygen species generation. The reaction between NO and superoxide anion generates the potent oxidant preoxynitrite, which leads to DNA damage. Other agents like MNNG, free radicals, hydrogen peroxide, hydroxyl radical or ionizing radiation cause DNA damage, which activate PARP-1. Step 2, PARP-1 activation catalyzes PAR polymer formation, which translocates from the nucleus to the mitochondria. Step 3, PAR polymer mediates AIF release from mitochondria and translocation to nucleus. Step 4, AIF causes chromatin condensation and large DNA fragmentation through an unknown mechanism.