title: Intra-mitochondrial poly(ADP-ribosylation) contributes to NAD+ depletion and cell death induced by oxidative stress.
abstract: Poly(ADP-ribosylation), primarily via poly(ADP-ribose) polymerase-1 (PARP-1), is a pluripotent cellular process important for maintenance of genomic integrity and RNA transcription in cells. However, during conditions of oxidative stress and energy depletion, poly(ADP-ribosylation) paradoxically contributes to mitochondrial failure and cell death. Although it has been presumed that poly(ADP-ribosylation) within the nucleus mediates this pathologic process, PARP-1 and other poly(ADP-ribosyltransferases) are also localized within mitochondria. To this end, the presence of PARP-1 and poly(ADP-ribosylation) were verified within mitochondrial fractions from primary cortical neurons and fibroblasts. Inhibition of poly(ADP-ribosylation) within the mitochondrial compartment preserved transmembrane potential (DeltaPsi(m)), NAD(+) content, and cellular respiration, prevented release of apoptosis-inducing factor, and reduced neuronal cell death triggered by oxidative stress. Treatment with liposomal NAD(+) also preserved DeltaPsi(m) and cellular respiration during oxidative stress. Furthermore, inhibition of poly(ADP-ribosylation) prevented intranuclear localization of apoptosis-inducing factor and protected neurons from excitotoxic injury; and PARP-1 null fibroblasts were protected from oxidative stress-induced cell death. Collectively these data suggest that poly(ADP-ribosylation) compartmentalized to the mitochondria can be converted from a homeostatic process to a mechanism of cell death when oxidative stress is accompanied by energy depletion. These data implicate intra-mitochondrial poly(ADP-ribosylation) as an important therapeutic target for central nervous system and other diseases associated with oxidative stress and energy failure.
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh, Safar Center for Resuscitation Research, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Du
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Zhang
authors.forename: Yong Y
authors.initials: YY
authors.lastname: Han
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Burke
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Steven H
authors.initials: SH
authors.lastname: Graham
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Carcillo
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
authors.forename: Robert S B
authors.initials: RS
authors.lastname: Clark
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D003374:Coumarins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D018698:Glutamic Acid / Q000737:chemistry; D007150:Immunohistochemistry; D008297:Male; D008564:Membrane Potentials; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism*; D009243:NAD / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D003374:Coumarins; D009243:NAD; C071383:5-iodo-6-amino-1,2-benzopyrone; D018698:Glutamic Acid; D011065:Poly(ADP-ribose) Polymerases