PT  - JOURNAL ARTICLE
AU  - Alano, Conrad C.
AU  - Garnier, Philippe
AU  - Ying, Weihai
AU  - Higashi, Youichirou
AU  - Kauppinen, Tiina M.
AU  - Swanson, Raymond A.
TI  - NAD<sup>+</sup> Depletion Is Necessary and Sufficient forPoly(ADP-Ribose) Polymerase-1-Mediated Neuronal Death
AID  - 10.1523/JNEUROSCI.5552-09.2010
DP  - 2010 Feb 24
TA  - The Journal of Neuroscience
PG  - 2967--2978
VI  - 30
IP  - 8
4099  - http://www.jneurosci.org/content/30/8/2967.short
4100  - http://www.jneurosci.org/content/30/8/2967.full
SO  - J. Neurosci.2010 Feb 24; 30
AB  - 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.