Implications of NAD<sup>+</sup> boosters in translational medicine

Kang, Baeki E.; Choi, Jun‐Yong; Stein, Sokrates; Ryu, Dongryeol

doi:10.1111/eci.13334

Cited by 23 publications

(24 citation statements)

References 109 publications

(145 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A Parp mutation improves mitochondrial function and restores neuronal health in Aβ-Arc-expressing flies The coenzyme NAD + is not only essential for energy metabolism but also acts as a co-substrate in biochemical reactions such as protein ADP-ribosylation (PAR), catalysed by PARPs, reviewed in [16]. We have previously shown that mitochondrial dysfunction in pink1 or parkin mutant flies, two genes implicated in Parkinson's disease, causes an increase in PAR levels.…”

Section: Identification Of a Metabolic Signature Linked To Nicotinate And Nam Metabolism In Flies Expressing Toxic Aβmentioning

confidence: 99%

Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease

Fedele

Celardo

et al. 2021

Cell Death Dis

View full text Add to dashboard Cite

Alzheimer’s disease is the most common age-related neurodegenerative disorder. Familial forms of Alzheimer’s disease associated with the accumulation of a toxic form of amyloid-β (Aβ) peptides are linked to mitochondrial impairment. The coenzyme nicotinamide adenine dinucleotide (NAD+) is essential for both mitochondrial bioenergetics and nuclear DNA repair through NAD+-consuming poly (ADP-ribose) polymerases (PARPs). Here we analysed the metabolomic changes in flies overexpressing Aβ and showed a decrease of metabolites associated with nicotinate and nicotinamide metabolism, which is critical for mitochondrial function in neurons. We show that increasing the bioavailability of NAD+ protects against Aβ toxicity. Pharmacological supplementation using NAM, a form of vitamin B that acts as a precursor for NAD+ or a genetic mutation of PARP rescues mitochondrial defects, protects neurons against degeneration and reduces behavioural impairments in a fly model of Alzheimer’s disease. Next, we looked at links between PARP polymorphisms and vitamin B intake in patients with Alzheimer’s disease. We show that polymorphisms in the human PARP1 gene or the intake of vitamin B are associated with a decrease in the risk and severity of Alzheimer’s disease. We suggest that enhancing the availability of NAD+ by either vitamin B supplements or the inhibition of NAD+-dependent enzymes such as PARPs are potential therapies for Alzheimer’s disease.

show abstract

Section: Identification Of a Metabolic Signature Linked To Nicotinate And Nam Metabolism In Flies Expressing Toxic Aβmentioning

confidence: 99%

Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease

Fedele

Celardo

et al. 2021

Cell Death Dis

View full text Add to dashboard Cite

show abstract

“…In conclusion, the present study furthers our understanding of the complex network of events that regulate iNAD+ content. Finally, it suggests that the therapeutic potential of the different NAD+-boosting strategies ( 67 ) might be significantly reduced in those tissues in which the NAD+-resetting response is functionally relevant. Of course, NAD+-supplementation strategies may still be of therapeutic relevance in conditions of iNAD+ deficiency.…”

Section: Discussionmentioning

confidence: 99%

SIRT1-dependent restoration of NAD+ homeostasis after increased extracellular NAD+ exposure

Buonvicino

Ranieri

Pittelli

et al. 2021

Journal of Biological Chemistry

View full text Add to dashboard Cite

In the last several years, NAD+ supplementation has emerged as an innovative and safe therapeutic strategy for a wide spectrum of disorders, including diabetes and neuropathy. However, critical questions remain as to how NAD+ and its precursors are taken up by cells, as well as the effects of long-lasting intracellular NAD+ (iNAD+) increases. Here, we investigated the kinetics of iNAD+ levels in different cell types challenged with prolonged exposure to extracellular NAD+ (eNAD+). Surprisingly, we found that after the initial increase, iNAD+ contents decreased back to control levels (iNAD+ resetting). Focusing our attention on HeLa cells, we found that oxygen and ATP consumption occurred with similar temporal kinetics after eNAD+ exposure. Using [ 3 H]NAD+ and [ 14 C]NAD+, we determined that NAD+ resetting was not due to increased dinucleotide extrusion but rather due to reduced uptake of cleaved NAD+ products. Indeed, eNAD+ exposure reduced the expression of the ecto-5′-nucleotidase CD73, the nicotinamide adenine mononucleotide transporter solute carrier family 12 member 8, and the nicotinamide riboside kinase. Interestingly, silencing the NAD+-sensor enzyme sirtuin 1 prevented eNAD+-dependent transcriptional repression of ecto-5′-nucleotidase, solute carrier family 12 member 8, and nicotinamide riboside kinase, as well as iNAD+ resetting. Our findings provide the first evidence for a sirtuin 1–mediated homeostatic response aimed at maintaining physiological iNAD+ levels in conditions of excess eNAD+ availability. These data may be of relevance for therapies designed to support the NAD+ metabolome via extracellular supplementation of the dinucleotide or its precursors.

show abstract

“…Given the vital role of NAD in many cellular processes, it is not surprising that NAD + levels were shown to be decreased in aged individuals and supplementation with NAD + precursors was proven to ameliorate age-related disorders, including neurodegenerative diseases [74][75][76]. In line with that, the function of NAD + -dependent enzymes, such as sirtuins and ARTs, was shown to change upon aging [77].…”

Section: Nad + Quantificationmentioning

confidence: 91%

Uncovering the Invisible: Mono-ADP-ribosylation Moved into the Spotlight

Hopp

Hottiger

2021

Cells

View full text Add to dashboard Cite

Adenosine diphosphate (ADP)-ribosylation is a nicotinamide adenine dinucleotide (NAD+)-dependent post-translational modification that is found on proteins as well as on nucleic acids. While ARTD1/PARP1-mediated poly-ADP-ribosylation has extensively been studied in the past 60 years, comparably little is known about the physiological function of mono-ADP-ribosylation and the enzymes involved in its turnover. Promising technological advances have enabled the development of innovative tools to detect NAD+ and NAD+/NADH (H for hydrogen) ratios as well as ADP-ribosylation. These tools have significantly enhanced our current understanding of how intracellular NAD dynamics contribute to the regulation of ADP-ribosylation as well as to how mono-ADP-ribosylation integrates into various cellular processes. Here, we discuss the recent technological advances, as well as associated new biological findings and concepts.

show abstract

Implications of NAD⁺ boosters in translational medicine

Cited by 23 publications

References 109 publications

Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease

Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease

SIRT1-dependent restoration of NAD+ homeostasis after increased extracellular NAD+ exposure

Uncovering the Invisible: Mono-ADP-ribosylation Moved into the Spotlight

Contact Info

Product

Resources

About

Implications of NAD+ boosters in translational medicine

Cited by 23 publications

References 109 publications

Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease

Parp mutations protect from mitochondrial toxicity in Alzheimer’s disease

SIRT1-dependent restoration of NAD+ homeostasis after increased extracellular NAD+ exposure

Uncovering the Invisible: Mono-ADP-ribosylation Moved into the Spotlight

Contact Info

Product

Resources

About

Implications of NAD⁺ boosters in translational medicine