The Role of ADP-Ribosylation in Mitochondria-Mediated Cell Death

Abstract

Poly(ADP)ribose (PAR) metabolism is essential to many cellular functions, including the maintenance of genomic integrity, the regulation of cell death mechanisms, as well as the regulation of gene expression. Recent work has uncovered many new players in the expanding effort to understand PAR metabolism and its cellular impact. PARP-1, the prototypical poly(ADP)ribose polymerase, was the first to be discovered, and has since been shown to be vital in the cellular response to DNA damage. Indeed, one report demonstrating that PARP-1 activation is required for apoptosis-inducing factor (AIF) release from mitochondria uncovered a novel link between DNA damage and signaling for cell death. The events following PARP activation, leading to signaling for AIF release, however, are still poorly understood. Based on our observations, we have developed a model to explain the nuclear/mitochondrial crosstalk that occurs following PARP activation. The work presented here answers several important questions regarding the relationship between ADP-ribose metabolism and mitochondria, including the role of PAR in signaling for the release of AIF, the presence of ADP-ribose metabolism protein members in mitochondria, and mitochondrial transcriptional effects following PARP activation. This work presents several novel findings, including the first report of a mitochondrial matrix isoform of poly(ADP-ribose) glycohydrolase (PARG) as well as direct evidence of mitochondria-associated PARP activity. Furthermore, it provides evidence for a novel effect of PARP-1 activation, in the specific transcriptional upregulation of the mitochondrial gene, NADH dehydrogenase, subunit 1 (ND1). Our data is consistent with the hypothesis that uncontrolled PARP activity results in energy metabolism dysfunction and cell death. Furthermore, it supports a model in which PARP activity is required for normal transcriptional responses in mitochondria following DNA damage. In total, this report adds to the body of work outlining the roles of PARP following DNA damage recognition and activation, demonstrating that ADP-ribose metabolism plays an important role in cell death regulation by both direct and indirect means.