Intra-mitochondrial poly(ADP-ribosylation) contributes to NAD+ depletion and cell death induced by oxidative stress

Lina Du, Xiaopeng Zhang, Yong Y. Han, Nancy A. Burke, Patrick M. Kochanek, Simon C. Watkins, Steven H. Graham, Joseph A. Carcillo, Csaba Szabo, Robert S B Clark

Research output: Contribution to journalArticle

256 Citations (Scopus)

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 (Δψm), 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 Δψm 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.

Original languageEnglish (US)
Pages (from-to)18426-18433
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number20
DOIs
StatePublished - May 16 2003
Externally publishedYes

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Oxidative stress
Cell death
NAD
Adenosine Diphosphate
Oxidative Stress
Cell Death
Poly(ADP-ribose) Polymerases
Apoptosis Inducing Factor
Cell Respiration
Mitochondria
Fibroblasts
Neurons
ADP Ribose Transferases
Central Nervous System Diseases
Neurology
Pathologic Processes
Transcription
Membrane Potentials
Maintenance
RNA

ASJC Scopus subject areas

  • Biochemistry

Cite this

Du, L., Zhang, X., Han, Y. Y., Burke, N. A., Kochanek, P. M., Watkins, S. C., ... Clark, R. S. B. (2003). Intra-mitochondrial poly(ADP-ribosylation) contributes to NAD+ depletion and cell death induced by oxidative stress. Journal of Biological Chemistry, 278(20), 18426-18433. https://doi.org/10.1074/jbc.M301295200

Intra-mitochondrial poly(ADP-ribosylation) contributes to NAD+ depletion and cell death induced by oxidative stress. / Du, Lina; Zhang, Xiaopeng; Han, Yong Y.; Burke, Nancy A.; Kochanek, Patrick M.; Watkins, Simon C.; Graham, Steven H.; Carcillo, Joseph A.; Szabo, Csaba; Clark, Robert S B.

In: Journal of Biological Chemistry, Vol. 278, No. 20, 16.05.2003, p. 18426-18433.

Research output: Contribution to journalArticle

Du, L, Zhang, X, Han, YY, Burke, NA, Kochanek, PM, Watkins, SC, Graham, SH, Carcillo, JA, Szabo, C & Clark, RSB 2003, 'Intra-mitochondrial poly(ADP-ribosylation) contributes to NAD+ depletion and cell death induced by oxidative stress', Journal of Biological Chemistry, vol. 278, no. 20, pp. 18426-18433. https://doi.org/10.1074/jbc.M301295200
Du, Lina ; Zhang, Xiaopeng ; Han, Yong Y. ; Burke, Nancy A. ; Kochanek, Patrick M. ; Watkins, Simon C. ; Graham, Steven H. ; Carcillo, Joseph A. ; Szabo, Csaba ; Clark, Robert S B. / Intra-mitochondrial poly(ADP-ribosylation) contributes to NAD+ depletion and cell death induced by oxidative stress. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 20. pp. 18426-18433.
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AU - Burke, Nancy A.

AU - Kochanek, Patrick M.

AU - Watkins, Simon C.

AU - Graham, Steven H.

AU - Carcillo, Joseph A.

AU - Szabo, Csaba

AU - Clark, Robert S B

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