Mitochondrial and nuclear cross talk in cell death: parthanatos

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear protein best known to facilitate DNA base excision repair. Recent work has expanded the physiologic functions of PARP-1, and it is clear that the full range of biologic actions of this important protein are not yet fully understood. Regulation of the product of PARP-1, poly(ADP-ribose) (PAR), is a dynamic process with PAR glycohydrolase playing the major role in the degradation of the polymer. Under pathophysiologic situations overactivation of PARP-1 results in unregulated PAR synthesis and widespread neuronal cell death. Once thought to be necrotic cell death resulting from energy failure, we have found that PARP-1-dependent cell death is dependent on the generation of PAR, which triggers the nuclear translocation of apoptosis-inducing factor resulting in caspase-independent cell death. This form of cell death is distinct from apoptosis, necrosis, or autophagy and is termed parthanatos. PARP-1-dependent cell death has been implicated in tissues throughout the body and in diseases afflicting hundreds of millions worldwide, including stroke, Parkinson's disease, heart attack, diabetes, and ischemia reperfusion injury in numerous tissues. The breadth of indications for PARP-1 injury make parthanatos a clinically important form of cell death to understand and control.

Figure 1

PARP-1 utilizes NAD⁺ as a substrate and builds-up PAR polymers on acceptor proteins. PAR generated by PARP-1 is hydrolysed by PARG into ADP-ribose or free PAR. In the process of PAR formation nicotinamine (NAM) is generated as a by product. NAM is a PARP inhibitor and may cause a negative feed back on PARP activity. NAM enters into NAD⁺ synthetic cycle nicotine mono nucleotide and ATP as precursors. The reaction requires phosphor ribosyl-1-pyrophosphate (PRPP). NAM can inhibit PARP-1 by negative feed back effect. Mild DNA nicks or breaks activate PARP to induce DNA repair via poly(ADPribosyl)ation process. When the DNA damage is beyond the threshold of poly(ADPribosyl)ation-mediated repair, excessive PAR generated kills the cells via the process of Parthanatos.

Figure 2

PARP-1 activation and role of PAR in Parthanatos. DNA damage in cell stress conditions leads to PARP-1 activation. Active PARP-1 uses NAD⁺ as a substrate and builds PAR on itself (auto-modification) and on various acceptor proteins (hetero-modification) in the nucleus. PARG can hydrolyze PAR in the nucleus to generate fee PAR or ADP-ribose. PAR accumulation induces cell death. PAR is mainly generated in the nucleus and translocates to cytosol either as attached polymer to poly(ADP-ribosyl)ated proteins or as a free polymer. Cytosolic isoforms of PARG can degrade PAR when present in optimal amounts in relation to PAR generated. In the cytosol PAR interacts with mitochondria to induce AIF release. On translocation to nucleus, AIF binds to DNA and mediates a large scale DNA fragmentation and cell death.