The Reciprocal Relationship between SIRT1 and PARPs during NAD+ Homeostasis and Metabolic Signaling in the Cell
(A) NAD+ is an essential coenzyme for sirtuin, PARP, and CD38 activity, all of which metabolize NAD+ into NAM. Glycolysis and the TCA cycle also consume available NAD+ for the production of NADH, providing reducing equivalents for either lactate dehydrogenase (LDH) or the ETC. Red font indicates environmental or physiological stimuli that activate sirtuins by increasing NAD+, while blue font indicates a reduction in NAD+, thereby diminishing sirtuin activity. NAM can be shunted away from NAD+ production following methylation by NNMT, a pathway activated by a HFD or with long-term or high doses of NAM, which can favor the development of a fatty liver, due to reductions in available methyl groups. In contrast, NNMT depletion by NNMT-antisense oligonucleotides in animals or mNAM supplementation in cells reduces NAM methylation. With a HFD, NAD+ can be reduced by elevating energy availability and NADH production, while exercise, fasting, and CR reverses this process providing more NAD+ for sirtuin activation and protein deacetylation. NR supplementation or intraperitoneal NMN increases NAD+ availability via the NAD+ salvage pathway in mice. Ultimately, SIRT1 induces mitochondrial biogenesis, energy expenditure, antioxidant defenses, and lifespan extension by a mechanism that involves the mitochondrial unfolded protein response (UPRmt). PARPs consume NAD+, reducing SIRT1 activity, by increasing PARylation of DNA and proteins during aging, cancer, neurodegeneration, and mitochondrial diseases. (B) SIRT1 negatively regulates PARP1 through the inhibition of transcription and possibly through deacetylation. Reciprocally, PARP1 inhibits SIRT1 by limiting NAD+ levels, while PARP2 directly inhibits SIRT1 transcription. Interestingly, PARP1 is required for the transcriptional co-activation of NF-κB, while SIRT1 inhibits NF-κB activity through the deacetylation of RelA/p65. In addition, PARP1 and SIRT1 oppositely regulate p53 nuclear accumulation and activation following cytotoxic stress. Since the Km of PARP1 for NAD+ is lower than that of SIRT1, as NAD+ levels drop following cell stress or senescence, SIRT1 becomes less effective at regulating PARP1, and inhibiting inflammation or cell death through the inactivation of NF-κB and p53. Dashed arrows indicate pathways that need further validation.