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- Title
NAD<sup>+</sup> Depletion Is Necessary and Sufficient for Poly(ADP-Ribose) Polymerase-1-Mediated Neuronal Death.
- Authors
Alano, Conrad C.; Garnier, Philippe; Weihai Ying; Higashi, Youichirou; Kauppinen, Tiina M.; Swanson, Raymond A.
- 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 P2X7-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.
- Subjects
NEURONS; CELL death; RIBOSE; ISCHEMIA; OXIDATIVE stress; MITOCHONDRIA
- Publication
Journal of Neuroscience, 2010, Vol 30, Issue 8, p2967
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.5552-09.2010