scholarly journals Nicotinamide adenine dinucleotide is transported into mammalian mitochondria

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Antonio Davila ◽  
Ling Liu ◽  
Karthikeyani Chellappa ◽  
Philip Redpath ◽  
Eiko Nakamaru-Ogiso ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Nicotinamide Adenine Dinucleotide ◽  
Mitochondrial Matrix ◽  
Pyridine Nucleotides ◽  
Nicotinamide Riboside ◽  
Isolated Mitochondria ◽  
Mitochondrial Inner Membrane ◽  
Fuel Selection ◽  
Nicotinamide Mononucleotide ◽  
Mammalian Mitochondria

Mitochondrial NAD levels influence fuel selection, circadian rhythms, and cell survival under stress. It has alternately been argued that NAD in mammalian mitochondria arises from import of cytosolic nicotinamide (NAM), nicotinamide mononucleotide (NMN), or NAD itself. We provide evidence that murine and human mitochondria take up intact NAD. Isolated mitochondria preparations cannot make NAD from NAM, and while NAD is synthesized from NMN, it does not localize to the mitochondrial matrix or effectively support oxidative phosphorylation. Treating cells with nicotinamide riboside that is isotopically labeled on the nicotinamide and ribose moieties results in the appearance of doubly labeled NAD within mitochondria. Analogous experiments with doubly labeled nicotinic acid riboside (labeling cytosolic NAD without labeling NMN) demonstrate that NAD(H) is the imported species. Our results challenge the long-held view that the mitochondrial inner membrane is impermeable to pyridine nucleotides and suggest the existence of an unrecognized mammalian NAD (or NADH) transporter.

scholarly journals Sources and Importance of Mitochondrial NAD

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 737-737
Author(s):  
Joseph Baur ◽  
Timothy Luongo ◽  
Jared Eller ◽  
Mu-Jie Lu ◽  
Caroline Perry ◽  
...  
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
Isotopic Labeling ◽  
Rodent Models ◽  
Mitochondrial Matrix ◽  
Mitochondrial Membranes ◽  
Respiratory Capacity ◽  
Beneficial Effects ◽  
Isolated Mitochondria ◽  
Basic Biology ◽  
Specific Regulation

Abstract Nicotinamide adenine dinucleotide (NAD) levels fall with age or disease, and rise with exercise or caloric restriction. Moreover, the demonstration that supplemental NAD precursors drive beneficial effects in rodent models has driven a resurgence in interest in the basic biology of this molecule. Although NAD is present in the mitochondrial matrix and critical to the function of the organelle, the source of mitochondrial NAD has been debated. We recently used isotopic labeling to demonstrate that direct uptake of intact NAD is one mechanism by which mitochondria are able to obtain this nucleotide. Here, we show that this activity is sufficient to restore respiratory capacity in NAD-deficient isolated mitochondria, and identify SLC25A51 as a carrier that can mediate the transport of NAD across mitochondrial membranes. Understanding the compartment-specific regulation of NAD will be crucial to understanding how cells and tissues adapt their metabolism to changes in NAD availability. Funding: DK098656 to J.A.B., GM126897 to L.A.C.

Nicotinamide adenine dinucleotide metabolism in plants. I. Intermediates of biosynthesis in wheat leaves and the effect of benzimidazole

1970 ◽  
Vol 48 (12) ◽  
pp. 2267-2278 ◽  
Author(s):  
H. R. Godavari ◽  
E. R. Waygood
Keyword(s):  
Nicotinic Acid ◽  
Nicotinamide Adenine Dinucleotide ◽  
Triticum Aestivum L ◽  
Total Radioactivity ◽  
Significant Loss ◽  
Nicotinamide Adenine ◽  
Nad Metabolism ◽  
Nicotinamide Riboside ◽  
Nicotinamide Mononucleotide ◽  
Wheat Leaves

Leaves of wheat (Triticum aestivum L. var. Selkirk) were incubated with nicotinic acid-7-14C and nicotinamide-7-14C for varying time periods from 5 min to 12 h. Aliquots of alcoholic extracts of leaves were subjected to paper chromatography and radioautography to isolate the intermediates of the synthesis and breakdown of nicotinamide adenine dinucleotide. Nine compounds were isolated quantitatively and identified as intermediates in the pathway of NAD metabolism. All the intermediates were labeled rapidly and the rapidity of labeling became a problem in rigorously proving the sequential operation of the pathway. The results indicate that the Preiss-Handler pathway: nicotinic acid→nicotinic acid mononucleotide→nicotinic acid adenine dinucleotide→NAD operates in wheat leaves. The degradation of NAD proceeded from NAD→nicotinamide mononucleotide→nicotinamide riboside→nicotinamide. Deamidation of the nicotinamide to nicotinic acid initiated a fresh cycle of biosynthesis. The total radioactivity recovered in the intermediates indicates that no measurable amount was lost to other metabolic pathways. Nicotinamide is recovered without significant loss and recycled. The rapid appearance of labeled nicotinamide indicates a possible interconversion of nicotinic acid and nicotinamide. About 80% of the radioactivity accumulated was present in trigonelline which is considered, on the basis of other evidence, to be a non-toxic form of nicotinic acid. Benzimidazole treatment of the leaves increased the incorporation of 14C into NADP.

scholarly journals How mitochondria produce reactive oxygen species

2008 ◽  
Vol 417 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Michael P. Murphy
Keyword(s):  
Reactive Oxygen Species ◽  
Oxidative Damage ◽  
Oxygen Species ◽  
Mitochondrial Matrix ◽  
Redox Signalling ◽  
Isolated Mitochondria ◽  
Mitochondrial Ros ◽  
Mammalian Mitochondria ◽  
O2 Production

The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies and contributes to retrograde redox signalling from the organelle to the cytosol and nucleus. Superoxide (O2•−) is the proximal mitochondrial ROS, and in the present review I outline the principles that govern O2•− production within the matrix of mammalian mitochondria. The flux of O2•− is related to the concentration of potential electron donors, the local concentration of O2 and the second-order rate constants for the reactions between them. Two modes of operation by isolated mitochondria result in significant O2•− production, predominantly from complex I: (i) when the mitochondria are not making ATP and consequently have a high Δp (protonmotive force) and a reduced CoQ (coenzyme Q) pool; and (ii) when there is a high NADH/NAD+ ratio in the mitochondrial matrix. For mitochondria that are actively making ATP, and consequently have a lower Δp and NADH/NAD+ ratio, the extent of O2•− production is far lower. The generation of O2•− within the mitochondrial matrix depends critically on Δp, the NADH/NAD+ and CoQH2/CoQ ratios and the local O2 concentration, which are all highly variable and difficult to measure in vivo. Consequently, it is not possible to estimate O2•− generation by mitochondria in vivo from O2•−-production rates by isolated mitochondria, and such extrapolations in the literature are misleading. Even so, the description outlined here facilitates the understanding of factors that favour mitochondrial ROS production. There is a clear need to develop better methods to measure mitochondrial O2•− and H2O2 formation in vivo, as uncertainty about these values hampers studies on the role of mitochondrial ROS in pathological oxidative damage and redox signalling.

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

2021 ◽  
Vol 22 (7) ◽  
pp. 3709
Author(s):  
Fiqri D. Khaidizar ◽  
Yasumasa Bessho ◽  
Yasukazu Nakahata
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
The Elderly ◽  
Cellular Level ◽  
Salvage Pathway ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Nicotinamide Riboside ◽  
Nicotinamide Mononucleotide ◽  
Age Related ◽  
Rate Limiting ◽  
Over Time

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.

scholarly journals The Inhibitory Effects of Nucleosides, Nicotinamide Adenine Dinucleotide, Adenosine 5'-Triphosphate, Inosine, Nicotinamide Riboside and Nicotinamide Mononucleotide Against α-Amylase and α-Glucosidase Enzymes

2020 ◽  
Vol 5 (3) ◽  
pp. 182-198
Author(s):  
Fatemeh Ghorbania ◽  
◽  
Masoomeh Ghorbani ◽  
Arezou Ghahghaee ◽  
Keyword(s):  
Adenosine Triphosphate ◽  
Nicotinamide Adenine Dinucleotide ◽  
Adenosine Diphosphate ◽  
Structural Features ◽  
Nicotinamide Adenine ◽  
Oh Groups ◽  
Nicotinamide Riboside ◽  
Nicotinamide Mononucleotide ◽  
Ic50 Values ◽  
Hydrolyzing Enzymes

Diabetes is a group of metabolic disorders characterized by a high blood sugar level over a prolonged period of time. Inhibition of carbohydrate hydrolyzing enzymes leads to decrease in the absorption of glucose which is considered as one of the effective managements of diabetes mellitus. Vegetable, fruit, milk and fish are good sources of nucleosides and inosine (INO), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) with versatile health benefits. The well-adapted structural features of these compounds for the inhibition/activation of enzymes include several available hydrogen bond (H-bond) acceptors and donors, flexible backbone and hydrophobic nature. The substrates of α-amylase (α-Amy) and α-Glucosidase (α-Glu), known as key absorbing enzymes, have functional groups (OH groups) resembling nucleosides. Therefore, the present study was conducted to evaluate the inhibitory properties of nucleosides against αAmy and α-Glu. The median inhibition concentration (IC50) values for α-Glu in the presence of adenosine (ADN), adenosine triphosphate (AMP), NR, INO, adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NAD), Adenosine diphosphate (ADP)-ribose, ADP-glucose and NMN were determined 208.6±3.8, 254.1±5.2, 177.7±4.8, 192.1±5.2, 215.9±2.7, 65.4±1.3, 63.4±2.2, 75.6±4.2 and 196.1±2.6, respectively. The IC50 values α-Amy in the presence of ADN, AMP, NR, INO, ATP, NAD, ADP-ribose, ADP-glucose and NMN were determined 145.3±2.4, 202.3±3.9, 127.7±4.8, 163.5±3.6, 185.3±1.2, 80.4±2.8, 64.8±4.7, 51.1±1.6 and 166.5±1.4, respectively. Moreover, the Ki values of NAD were calculated as 13.8±0.8 and 18.6±2.4 µM for α-Glu and α-Amy in a competitive-mode and noncompetitive -mode inhibition. In addition, to communicate with the active site of α-Glu and α-Amy respectively, NR presented a binding energy of -7.8 and -6.8 kcal/mol, INO -7.3 and -6.9, ATP -8.3 and -7.3, NAD -10.0 and -8.5, ADP-ribose -8.7 and -7.4, ADP-glucose -8.9 and -7.6, cAMP -6.6 and -6.3 and NMN -6.8 and -7.0 kcal/mol. These antioxidant inhibitors may be potential anti-diabetic drugs, not only to reduce glycemic index, but also to limit the activity of the major reactive oxygen species (ROS) producing pathways. Key words: Nucleosides, NAD, hydrolyzing enzymes, enzyme inhibition, hyperglycemia

scholarly journals NAD+ biosynthesis, aging, and disease

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 132 ◽  
Author(s):  
Sean Johnson ◽  
Shin–ichiro Imai
Keyword(s):  
Mental Disorders ◽  
Nicotinamide Adenine Dinucleotide ◽  
Metabolic Disorders ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Proof Of Concept ◽  
Nicotinamide Riboside ◽  
Aging Intervention ◽  
Nicotinamide Mononucleotide ◽  
Downstream Effectors

Nicotinamide adenine dinucleotide (NAD+) biosynthesis and its regulation have recently been attracting markedly increasing interest. Aging is marked by a systemic decrease in NAD+ across multiple tissues. The dysfunction of NAD+ biosynthesis plays a critical role in the pathophysiologies of multiple diseases, including age-associated metabolic disorders, neurodegenerative diseases, and mental disorders. As downstream effectors, NAD+-dependent enzymes, such as sirtuins, are involved in the progression of such disorders. These recent studies implicate NAD+ biosynthesis as a potential target for preventing and treating age-associated diseases. Indeed, new studies have demonstrated the therapeutic potential of supplementing NAD+ intermediates, such as nicotinamide mononucleotide and nicotinamide riboside, providing a proof of concept for the development of an effective anti-aging intervention.

scholarly journals Nicotinamide Mononucleotide: Exploration of Diverse Therapeutic Applications of a Potential Molecule

Biomolecules ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 34 ◽  
Author(s):  
Saikat Kumar Poddar ◽  
Ali Ehsan Sifat ◽  
Sanjana Haque ◽  
Noor Ahmed Nahid ◽  
Sabiha Chowdhury ◽  
...  
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
Biosynthetic Pathway ◽  
The Other ◽  
Preclinical Studies ◽  
Salvage Pathway ◽  
Pharmacological Activities ◽  
Nicotinamide Riboside ◽  
Nad Biosynthesis ◽  
Nicotinamide Mononucleotide ◽  
Subsequent Conversion

Nicotinamide mononucleotide (NMN) is a nucleotide that is most recognized for its role as an intermediate of nicotinamide adenine dinucleotide (NAD+) biosynthesis. Although the biosynthetic pathway of NMN varies between eukaryote and prokaryote, two pathways are mainly followed in case of eukaryotic human—one is through the salvage pathway using nicotinamide while the other follows phosphorylation of nicotinamide riboside. Due to the unavailability of a suitable transporter, NMN enters inside the mammalian cell in the form of nicotinamide riboside followed by its subsequent conversion to NMN and NAD+. This particular molecule has demonstrated several beneficial pharmacological activities in preclinical studies, which suggest its potential therapeutic use. Mostly mediated by its involvement in NAD+ biosynthesis, the pharmacological activities of NMN include its role in cellular biochemical functions, cardioprotection, diabetes, Alzheimer's disease, and complications associated with obesity. The recent groundbreaking discovery of anti-ageing activities of this chemical moiety has added a valuable essence in the research involving this molecule. This review focuses on the biosynthesis of NMN in mammalian and prokaryotic cells and mechanism of absorption along with the reported pharmacological activities in murine model.

scholarly journals Creating enzymes and self-sufficient cells for biosynthesis of the non-natural cofactor nicotinamide cytosine dinucleotide

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xueying Wang ◽  
Yanbin Feng ◽  
Xiaojia Guo ◽  
Qian Wang ◽  
Siyang Ning ◽  
...  
Keyword(s):  
Biological Sciences ◽  
Escherichia Coli ◽  
Nicotinamide Adenine Dinucleotide ◽  
Chemical Biology ◽  
Reduced Form ◽  
Redox Transformations ◽  
Nicotinamide Mononucleotide ◽  
Self Sufficiency ◽  
Binding Pockets ◽  
Pathway Regulation

AbstractNicotinamide adenine dinucleotide (NAD) and its reduced form are indispensable cofactors in life. Diverse NAD mimics have been developed for applications in chemical and biological sciences. Nicotinamide cytosine dinucleotide (NCD) has emerged as a non-natural cofactor to mediate redox transformations, while cells are fed with chemically synthesized NCD. Here, we create NCD synthetase (NcdS) by reprograming the substrate binding pockets of nicotinic acid mononucleotide (NaMN) adenylyltransferase to favor cytidine triphosphate and nicotinamide mononucleotide over their regular substrates ATP and NaMN, respectively. Overexpression of NcdS alone in the model host Escherichia coli facilitated intracellular production of NCD, and higher NCD levels up to 5.0 mM were achieved upon further pathway regulation. Finally, the non-natural cofactor self-sufficiency was confirmed by mediating an NCD-linked metabolic circuit to convert L-malate into D-lactate. NcdS together with NCD-linked enzymes offer unique tools and opportunities for intriguing studies in chemical biology and synthetic biology.

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