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How NAD+ works?
Dec 07, 2021

Regulatory effects of NAD+/Sirt3 pathway on mitochondrial function and stem cell senescence

1.NAD+ /Sirt3 pathway

Sirtuins family is a class of protein deacetylases that depend on NAD+, which are involved in the regulation of individual growth, development, survival, aging, metabolism, and disease occurrence. As a member of the Sirtuins family, Sirt3 is an important NAD+-dependent deacetylase in mitochondria. Under cellular stress, the long-chain Sirt3 is transferred from the nucleus to the mitochondria under the action of the mitochondrial localization signal and is cut into short chains of 28kDa. Sirt3 has a wide range of biological functions, and its function is closely related to the level of NAD+ in the cell. In neurodegenerative diseases, Sirt3 can effectively improve the abnormality of mitochondrial function. As NAD+ depletion increases the acetylation level of the Sirt3 target protein, exogenous NMN can reverse the above process by up-regulating NAD+ levels in the nucleus and mitochondria. In addition, the depletion of NAD+ in the mitochondria caused by the accumulation of NADH, the inactivation of mitochondrial Sirt3, and the loss of mitochondrial electron transport chain complex I can also be corrected by supplementing NMN. Therefore, the intermediate product of NAD+ synthesis may function through the reactivation of Sirtuins or the reactivation of other NAD+-dependent enzymes.

2. The regulatory effect of NAD+/Sirt3 pathway on mitochondrial function

As an NAD+-dependent deacetylase in mitochondria, Sirt3 can regulate the production of ATP and the electron transport process of mitochondria. Although Sirt3 can be distributed in mitochondria, nucleus, and cytoplasm, only the short-chain Sirt3 that exists in mitochondria has deacetylase activity, so mitochondria are generally considered to be the most important subcellular distribution location of Sirt3. The acetylation level of mitochondrial proteins will be affected and regulated by NAD+, which is a key molecule that can affect the function of mitochondria. Sirt3 can directly regulate the activity of mitochondrial acetylase through NAD+-dependent deacetylation, and then regulate mitochondrial functions, such as mitochondrial biosynthesis, ROS metabolism, ATP production, and mitochondrial integrity. Sirt3 can interact with at least one of the known subunits in the electron transport chain complex I (such as the 39kDa protein NDUFA9). When Sirt3 is lacking, the acetylation level of certain subunits in the complex I increases, which in turn affects mitochondrial oxidative phosphoric acid化 level. In addition, Sirt3 can also regulate the activity of various metabolic enzymes in mitochondria, thereby regulating the metabolism of mitochondria. Therefore, Sirt3 has always been an important drug target for research, but so far, no effective pathways and drugs have been found to activate Sirt3.

3. The regulatory effect of NAD+/Sirt3 pathway on stem cell senescence

Sirt3 can not only regulate various metabolic processes in the body by deacetylating various proteins in the mitochondria, but also reduce the level of mitochondria and intracellular ROS by participating in oxidative stress, thereby improving mitochondrial metabolism and inhibiting cell aging. Studies have shown that there is a direct connection between Sirt3 and human lifespan. Sirt3 is also related to the occurrence of metabolic diseases, cardiovascular diseases, aging, and degenerative diseases in the elderly. The expression of Sirt3 is positively regulated by the EphB2/c-Src signaling pathway and the Nrf2 gene. Sirt3 slows the aging of MSCs by down-regulating the level of ROS in mitochondria. The expression of Sirt3 is down-regulated during the aging process of stem cells. The use of Sirt3 for anti-stem cell aging research can be used as a new strategy to improve the efficacy of stem cell therapy.

It is reported in the literature that overexpression of NMNAT can reverse the senescence phenotype in the process of somatic cell reprogramming, and delay the replicative senescence of MSCs by up-regulating NAD+ level and Sirt3 activity in mitochondria. In summary, Sirt3 can be used as an effective therapeutic target in the process of using NAD+ strategies to delay stem cell aging and treat aging-related diseases.

nad powder

The main metabolic pathways of NAD are as follows:

NAM and NR are converted into NMN by NAMPT and NRKs, respectively. NMN and NaMN et al. (Ummarino et al., 2017, Marinescu et al., 2018). These precursors exist in the extracellular environment and can be transported through the plasma membrane where they are used (Spimnleretal, 2013, Kato and Lin, 2014). CD73 is cleaved to produce NMN, CD73 can be cleaved again to produce NR, and CD38 or CD157 can be cleaved to produce NAM (Ratajczak et al, 2016). As shown in the figure below, the level of NAD+ in cells may be caused by activators of the recycling pathway (green) or inhibitors of NAD+-consuming enzymes such as CD38, PARPs, and SARM1 (red)

how nad+ works

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