NAD⁺Depletion Is Necessary and Sufficient forPoly(ADP-Ribose) Polymerase-1-Mediated Neuronal Death

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 ϩ 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 ϩ to restore neuronal NAD ϩ levels after PARP-1 activation. Exogenous NAD ϩ was found to enter neurons through P2X 7 -gated channels. Restoration of cytosolic NAD ϩ 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 ϩ with NAD ϩ glycohydrolase produced a block in glycolysis inhibition, mitochondrial depolarization, AIF translocation, and neuron death, independent of PARP-1 activation. These results establish NAD ϩ depletion as a causal event in PARP-1-mediated cell death and place NAD ϩ depletion and glycolytic failure upstream of mitochondrial AIF release.

Prevention of Acute/Severe Hypoglycemia-Induced Neuron Death by Lactate Administration

“…Therefore, given this fact, how can lactate administration have a neuroprotective effect in this situation? We suggest the following explanation: it has been previously suggested that PARP-1 consumes the cytosolic NAD + pool, but does not consume the mitochondrial NAD + pool until the point that mitochondrial permeability transition occurs (Alano et al, 2010). Thus, during the first few hours or so after extensive PARP-1 activation, the mitochondria remain capable of respiration but the cytosol cannot metabolize glucose.…”

Transcriptional Reprogramming and Resistance to Colonic Mucosal Injury in Poly(ADP-ribose) Polymerase 1 (PARP1)-deficient Mice

“…These extracellular ADP-ribosyl-transferases are thought to act primarily as danger sensors, which react to elevated NAD ϩ concentrations resulting from tissue injury and cell death during acute inflammation; ART1 to down-modulate the cytotoxic effects of defensin 1␣ (27) and ART2 to increase T cell sensitivity to NAD ϩ -induced cell death by increasing the activity of the P2X7 calcium channel (28). Intracellular (cytoplasmic and nuclear) PARP1 is known for protection against genomic instability but also controls several forms of cell death, the effect attributed to energetic failure due to NAD ϩ depletion (29), activation of mitochondrial apoptosis inducible factor via its PAR-binding domain (30), or through activation of redoxsensitive cation channel TRPM2 (31) among other mechanisms. Therefore, the protection we observed in Parp1 Ϫ/Ϫ mice from DSS-mediated colitis, a model reliant on a direct toxic and pro-apoptotic effect on colonic epithelial cells (32), could be attributed to the resistance of the colonocytes to DSS-related cytotoxicity.…”

DNA strand break repair and neurodegeneration

“…Activation of PARP at SSBs can trigger another mechanism of cell death. Prolonged activation leads to accumulation of cellular poly(ADP-ribose) (PAR) and depletion of NAD + , which can stimulate the release of apoptosis-inducing factor from mitochondria, resulting in a PARPdependent, p53-independent, form of cell death known as parthanatos [152][153][154]. Neuronal cells seem to be particularly sensitive to PARP-induced cell death, as illustrated in models of cerebral ischemia [155,156].…”