NAD+ depletion is necessary and sufficient for poly(ADP-ribose) polymerase-1-mediated neuronal death.
J Neurosci
; 30(8): 2967-78, 2010 Feb 24.
Article
en En
| MEDLINE
| ID: mdl-20181594
ABSTRACT
Poly(ADP-ribose)-1 (PARP-1) is a key mediator of cell death in excitotoxicity, ischemia, and oxidative stress. PARP-1 activation leads to cytosolic NAD(+) depletion and mitochondrial release of apoptosis-inducing factor (AIF), but the causal relationships between these two events have been difficult to resolve. Here, we examined this issue by using extracellular NAD(+) to restore neuronal NAD(+) levels after PARP-1 activation. Exogenous NAD(+) was found to enter neurons through P2X(7)-gated channels. Restoration of cytosolic NAD(+) by this means prevented the glycolytic inhibition, mitochondrial failure, AIF translocation, and neuron death that otherwise results from extensive PARP-1 activation. Bypassing the glycolytic inhibition with the metabolic substrates pyruvate, acetoacetate, or hydroxybutyrate also prevented mitochondrial failure and neuron death. Conversely, depletion of cytosolic NAD(+) with NAD(+) glycohydrolase produced a block in glycolysis inhibition, mitochondrial depolarization, AIF translocation, and neuron death, independent of PARP-1 activation. These results establish NAD(+) depletion as a causal event in PARP-1-mediated cell death and place NAD(+) depletion and glycolytic failure upstream of mitochondrial AIF release.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Poli(ADP-Ribosa) Polimerasas
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NAD
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Degeneración Nerviosa
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Neuronas
Límite:
Animals
Idioma:
En
Revista:
J Neurosci
Año:
2010
Tipo del documento:
Article