RT Journal Article
SR Electronic
T1 NAD<sup>+</sup> Depletion Is Necessary and Sufficient forPoly(ADP-Ribose) Polymerase-1-Mediated Neuronal Death
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 2967
OP 2978
DO 10.1523/JNEUROSCI.5552-09.2010
VO 30
IS 8
A1 Alano, Conrad C.
A1 Garnier, Philippe
A1 Ying, Weihai
A1 Higashi, Youichirou
A1 Kauppinen, Tiina M.
A1 Swanson, Raymond A.
YR 2010
UL http://www.jneurosci.org/content/30/8/2967.abstract
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.