Intra-mitochondrial poly(ADP-ribosylation) contributes to NAD+ depletion and cell death induced by oxidative stress.
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.
Du
Lina
L
Department of Critical Care Medicine, University of Pittsburgh, Safar Center for Resuscitation Research, Pittsburgh, Pennsylvania 15260, USA.
Zhang
Xiaopeng
X
Han
Yong Y
YY
Burke
Nancy A
NA
Kochanek
Patrick M
PM
Watkins
Simon C
SC
Graham
Steven H
SH
Carcillo
Joseph A
JA
Szabó
Csaba
C
Clark
Robert S B
RS
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
D003374:Coumarins; D009243:NAD; C071383:5-iodo-6-amino-1,2-benzopyrone; D018698:Glutamic Acid; D011065:Poly(ADP-ribose) Polymerases