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Cell Structure and Cell Death

Updated January 11, 2022
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Cell Structure and Cell Death essay

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According to the suicide hypothesis, PARP-1 kills primarily by NAD+ depletion. The suicide hypothesis stems from studies showing that PARP-1 overactivation causes energy depletion. Indeed, inhibiting PARP-1 through pharmacological inhibitors or genetic deletion restores NAD+ levels and viability. In neurons for example, different neuronal populations treated with a variety of toxic stimuli exhibit protection and concomitant energy preservation with PARP inhibitors. Moreover, PARP-1 KO mice, which are resistant to transient cerebral ischemia-induced damage, exhibit reduced PAR and preserved NAD+ levels.

Based on what is known regarding bioenergetics, NAD+ depletion causes ATP depletion; and the resulting drop in cellular energy leads to cell demise. NAD+ is known to be a cofactor in several cellular metabolic processes needed for generating ATP such as glycolysis and the tricarboxylic acid cycle. In addition, NAD+ resynthesis requires at least 2-4 molecules of ATP while NAD+ depletion blocks glyceraldehyde 3-dehydrogenase activity leading to the cell investing ATP in glycolysis, but without the return in NAD+.

Thus, in support of the suicide hypothesis, PARP-1 activation leads to a block in the glycolysis. Indeed, replenishment of glycolytic and tricarboxylic acid cycle (TCA cycle) intermediates and substrates such as alpha-ketoglutarate or pyruvate, are neuroprotective. Also, administering NAD+ to cells or overexpression of NAD+ biosynthetic genes seem to rescue PARP-1 dependent cell death, suggesting that indeed, the NAD+ decline associated with PARP-1 overactivation can cause cell demise.

However, NAD+ replenishment probably prevents cell death through SIRT1 which is unrelated to energy levels. Recent findings suggest that the compartmentalization of NAD+ within cells also must be considered when evaluating death induced by NAD+ depletion. The mitochondrial pool of NAD+ appears to be more relevant for cell death rather than the cytosolic and nuclear pools, as cell death is rescued upon preservation of NAD+ in the mitochondria by cyclosporin A, or replenishment of NAD+ by overexpression of the biosynthetic nicotinic acid mononucleotide adenylyl transferase (Namnt).

The drop in NAD+ levels following PARP-1 overactivation reflects whole cell NAD+. Thus, conclusions made from these studies need to be reexamined in light of the recent finding that the mitochondrial levels of NAD+ remain at physiological levels following genotoxic stress and can support viability even when nuclear and cytoplasmic pools of NAD+ are depleted. Whether PARP-1 dependent cell death exclusively depends on mitochondrial NAD+ depletion remains to be determined, since overexpression of Namnt to replenish mitochondrial stores of NAD+ leads to a partial rescue of cell death only.

Reduction in cell death by cyclosporin A may also not be attributed solely to NAD+ preservation in the mitochondria, as it blocks mitochondrial permeability transition, which in itself is an important player in cell death signaling.Several studies question whether PARP-1 overactivation kills primarily by NAD+ depletion. Paschen et al showed that NAD+ decline does not always correlate with ATP decline in a model of ischemia reperfusion. Moreover, Goto et al showed that PARP-1 KO mice have reduced infarct size after MCAO ischemia compared with wild type animals, but there is no difference between groups in the changes in the energy status as measured by the water diffusion coefficient.

Also, Bax and calpain KO cells are protected from N-methyl-N′-nitroN-nitrosoguanidine (MNNG) to the same degree as wild-type controls treated with the PARP inhibitor DPQ (45). This is in spite of a massive drop in the NAD+ levels in Bax and calpain KO cells that is not seen in the DPQ-treated cells. These findings suggest that NAD+ depletion due to PARP-1 activation is not sufficient to account for cell demise.

Cell Structure and Cell Death essay

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Cell Structure and Cell Death. (2022, Jan 11). Retrieved from https://samploon.com/cell-structure-and-cell-death/

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