Bacteria Boost Mammalian Host NAD Metabolism by Engaging the Deamidated Biosynthesis Pathway

Shats, Igor; Williams, Jason; Liu, Juan; Makarov, Mikhail V.; Wu, Xiaoyue; Lih, Fred B.; Deterding, Leesa J.; Lim, Chaemin; Xu, Xiaojiang; Randall, Thomas A.; Lee, Ethan; Li, Wenling; Fan, Wei; Li, Jianliang; Sokolsky-Papkov, Marina; Kabanov, Alexander V.; Li, Leping; Migaud, Marie E.; Locasale, Jason W.; Li, Xiaoling

doi:10.1016/j.cmet.2020.02.001

Cited by 158 publications

(180 citation statements)

References 68 publications

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“…We performed mass spectrometry (MS) analysis to differentiate between NADH and NADPH changes in the whole cell, using relative quantification to show the more dynamic behavior [ 40 ]. We observed a gradual increase in NAD + (3 fold) and NADH (2.3 fold) levels in HEK293T at 1 h, which then returned to levels comparable to control after 4 and 24 h of NRH exposure ( Fig 6A and 6B ).…”

Section: Resultsmentioning

confidence: 99%

Dihydronicotinamide riboside promotes cell-specific cytotoxicity by tipping the balance between metabolic regulation and oxidative stress

et al. 2020

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Nicotinamide adenine dinucleotide (NAD+), the essential cofactor derived from vitamin B3, is both a coenzyme in redox enzymatic processes and substrate in non-redox events; processes that are intimately implicated in all essential bioenergetics. A decrease in intracellular NAD+ levels is known to cause multiple metabolic complications and age-related disorders. One NAD+ precursor is dihydronicotinamide riboside (NRH), which increases NAD+ levels more potently in both cultured cells and mice than current supplementation strategies with nicotinamide riboside (NR), nicotinamide mononucleotide (NMN) or vitamin B3 (nicotinamide and niacin). However, the consequences of extreme boosts in NAD+ levels are not fully understood. Here, we demonstrate the cell-specific effects of acute NRH exposure in mammalian cells. Hepatocellular carcinoma (HepG3) cells show dose-dependent cytotoxicity when supplemented with 100–1000 μM NRH. Cytotoxicity was not observed in human embryonic kidney (HEK293T) cells over the same dose range of NRH. PUMA and BAX mediate the cell-specific cytotoxicity of NRH in HepG3. When supplementing HepG3 with 100 μM NRH, a significant increase in ROS was observed concurrent with changes in the NAD(P)H and GSH/GSSG pools. NRH altered mitochondrial membrane potential, increased mitochondrial superoxide formation, and induced mitochondrial DNA damage in those cells. NRH also caused metabolic dysregulation, altering mitochondrial respiration. Altogether, we demonstrated the detrimental consequences of an extreme boost of the total NAD (NAD+ + NADH) pool through NRH supplementation in HepG3. The cell-specific effects are likely mediated through the different metabolic fate of NRH in these cells, which warrants further study in other systemic models.

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Section: Resultsmentioning

confidence: 99%

Dihydronicotinamide riboside promotes cell-specific cytotoxicity by tipping the balance between metabolic regulation and oxidative stress

et al. 2020

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“…NAMPT modulates processes involved in the pathogenesis of obesity and related disorders by influencing the oxidative stress response [ 12 ], is often overexpressed in tumor tissues, and potentially contributes to the ability of cancer cells to resist oxidative stress [ 19 ]. The levels of NAMPT decrease with aging due to chronic inflammation, oxidative stress, and DNA damage [ 20 ]. In the cardiovascular system, NAMPT exacerbates atherosclerotic inflammation and promotes atherosclerosis development in ApoE mice [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

NAMPT/SIRT1 Attenuate Ang II-Induced Vascular Remodeling and Vulnerability to Hypertension by Inhibiting the ROS/MAPK Pathway

Zhou

Zhang

Bolor-Erdene

et al. 2020

Oxidative Medicine and Cellular Longevity

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Hypertension is characterized by endothelial dysfunction, vascular remodeling, and rearrangement of the extracellular matrix. Besides, the pathogenesis of hypertension is closely related to excess generation of reactive oxygen species (ROS). Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis that influences the activity of NAD-dependent enzymes, such as sirtuins, which possess NAD-dependent protein deacetylase activity and cleave NAD during the deacetylation cycle. Recently, NAMPT has been shown to play a crucial role in various diseases associated with oxidative stress. However, the function and regulation of NAMPT in hypertension have not been extensively explored. In the present study, we identified NAMPT as a crucial regulator of hypertension, because NAMPT expression was significantly downregulated in both patients with hypertension and experimental animals. NAMPT knockout (NAMPT+/-) mice exhibited a significantly higher blood pressure and ROS levels after stimulation with angiotensin II (Ang II) than wild-type mice, and the administration of recombinant human NAMPT (rhNAMPT) reversed this effect. In vivo, overexpression of NAMPT protected against angiotensin II- (Ang II-) induced hypertension by inhibiting ROS production via sirtuin 1 in mouse aortic endothelial cells (MAECs) and mouse aortic vascular smooth muscle cells (MOVAs). In turn, NAMPT alleviated the ROS-induced mitogen-activated protein kinase (MAPK) pathway. In conclusion, NAMPT might be a novel biomarker and a therapeutic target in hypertension.

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“…It is interesting to note the NAD + boosting effect of these supplementations might not be as straight forward as initially thought due to the recent discovery that gut microbiota may also play a role in the NAD + boosting effect of dietary NAM. Shats and colleagues recently reported that nicotinamidase (PncA) produced by microbes in the gut actively converts NAM to NA [ 73 ]. NA is then taken up by colonic epithelial cells and further converted to NAD + .…”

Section: Supplementation Of Nad + and Its Precumentioning

confidence: 99%

“…This essentially reroutes the NAM from NAD + salvage pathway to the Preiss–Handler pathway. Furthermore, by tracing the fate of isotope-labeled NAM after treatments, NAD + molecules produced through this mode of NAD + biosynthesis have also been found to represent the major portion of the elevated NAD + pool in murine hepatic cells [ 73 ]. This demonstrated that a host–microbe metabolic interaction can influence the efficacy of certain NAD + boosting nutraceuticals.…”

Section: Supplementation Of Nad + and Its Precumentioning

confidence: 99%

Nicotinamide Phosphoribosyltransferase as a Key Molecule of the Aging/Senescence Process

Khaidizar

Bessho

Nakahata

2021

IJMS

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Aging is a phenomenon underlined by complex molecular and biochemical changes that occur over time. One of the metabolites that is gaining strong research interest is nicotinamide adenine dinucleotide, NAD+, whose cellular level has been shown to decrease with age in various tissues of model animals and humans. Administration of NAD+ precursors, nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), to supplement NAD+ production through the NAD+ salvage pathway has been demonstrated to slow down aging processes in mice. Therefore, NAD+ is a critical metabolite now understood to mitigate age-related tissue function decline and prevent age-related diseases in aging animals. In human clinical trials, administration of NAD+ precursors to the elderly is being used to address systemic age-associated physiological decline. Among NAD+ biosynthesis pathways in mammals, the NAD+ salvage pathway is the dominant pathway in most of tissues, and NAMPT is the rate limiting enzyme of this pathway. However, only a few activators of NAMPT, which are supposed to increase NAD+, have been developed so far. In this review, we will focus on the importance of NAD+ and the possible application of an activator of NAMPT to promote successive aging.

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Bacteria Boost Mammalian Host NAD Metabolism by Engaging the Deamidated Biosynthesis Pathway

Cited by 158 publications

References 68 publications

Dihydronicotinamide riboside promotes cell-specific cytotoxicity by tipping the balance between metabolic regulation and oxidative stress

Dihydronicotinamide riboside promotes cell-specific cytotoxicity by tipping the balance between metabolic regulation and oxidative stress

NAMPT/SIRT1 Attenuate Ang II-Induced Vascular Remodeling and Vulnerability to Hypertension by Inhibiting the ROS/MAPK Pathway

Nicotinamide Phosphoribosyltransferase as a Key Molecule of the Aging/Senescence Process

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