The CD38 glycohydrolase and the NAD sink: implications for pathological conditions

Zeidler, Julianna D.; Hogan, Kelly A.; Agorrody, Guilherme; Peclat, Thais; Kashyap, Sonu; Kanamori, Karina S.; Gomez, Lilian Sales; Mazdeh, Delaram Z.; Warner, Gina M.; Thompson, Katie L.; Chini, Claudia C.S.; Chini, Eduardo N.

doi:10.1152/ajpcell.00451.2021

Cited by 36 publications

(45 citation statements)

References 330 publications

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“…Conversely, cells overexpressing CD38 showed reductions in NAD + levels [ 57 ]. Changes in the expression of CD38 have been proposed to play a major role in NAD + homeostasis in situations of inflammation, aging and senescence [ 58 ].…”

Section: Nad + and Its Decline In Diseasementioning

confidence: 99%

Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations

Cercillieux

Ciarlo

Cantó

2022

Cell. Mol. Life Sci.

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Alterations in cellular nicotinamide adenine dinucleotide (NAD+) levels have been observed in multiple lifestyle and age-related medical conditions. This has led to the hypothesis that dietary supplementation with NAD+ precursors, or vitamin B3s, could exert health benefits. Among the different molecules that can act as NAD+ precursors, Nicotinamide Riboside (NR) has gained most attention due to its success in alleviating and treating disease conditions at the pre-clinical level. However, the clinical outcomes for NR supplementation strategies have not yet met the expectations generated in mouse models. In this review we aim to provide a comprehensive view on NAD+ biology, what causes NAD+ deficits and the journey of NR from its discovery to its clinical development. We also discuss what are the current limitations in NR-based therapies and potential ways to overcome them. Overall, this review will not only provide tools to understand NAD+ biology and assess its changes in disease situations, but also to decide which NAD+ precursor could have the best therapeutic potential.

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Section: Nad + and Its Decline In Diseasementioning

confidence: 99%

Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations

Cercillieux

Ciarlo

Cantó

2022

Cell. Mol. Life Sci.

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“…Recent studies suggested that NAD + -consuming enzymes may also play a regulatory role in aging-mediated NAD + depletion. These NAD + -consuming enzymes are sirtuins, poly (ADP-ribose) polymerases (PARPs), Sterile Alpha and TIR Motif Containing 1 (SARM1), and the ectoenzymes CD38 and CD157 [ 114 , 115 ] .…”

Section: The Balance Between Nad + Biosynthesis An...mentioning

confidence: 99%

Cancer treatment-induced NAD+ depletion in premature senescence and late cardiovascular complications

Banerjee¹,

Olmsted-Davis²,

Deswal³

et al. 2022

J Cardiovasc Aging

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Numerous studies have revealed the critical role of premature senescence induced by various cancer treatment modalities in the pathogenesis of aging-related diseases. Senescence-associated secretory phenotype (SASP) can be induced by telomere dysfunction. Telomeric DNA damage response induced by some cancer treatments can persist for months, possibly accounting for long-term sequelae of cancer treatments. Telomeric DNA damage-induced mitochondrial dysfunction and increased reactive oxygen species production are hallmarks of premature senescence. Recently, we reported that the nucleus-mitochondria positive feedback loop formed by p90 ribosomal S6 kinase (p90RSK) and phosphorylation of S496 on ERK5 (a unique member of the mitogen-activated protein kinase family that is not only a kinase but also a transcriptional co-activator) were vital signaling events that played crucial roles in linking mitochondrial dysfunction, nuclear telomere dysfunction, persistent SASP induction, and atherosclerosis. In this review, we will discuss the role of NAD+ depletion in instigating SASP and its downstream signaling and regulatory mechanisms that lead to the premature onset of atherosclerotic cardiovascular diseases in cancer survivors.

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“…Decreased cellular NAD + levels also blunt beneficial signaling through sirtuin NAD + -dependent protein deacetylases [ 163 ]. In mice, the decreased NAD + levels that occur with aging are largely due to increased levels and activity of the CD38 enzyme, which is most highly expressed in macrophages and hydrolyzes NAD + as well as its direct precursor nicotinamide mononucleotide (NMN) both intracellularly and extracellularly [ 164 ]. The activity of NAMPT also declines slightly with aging [ 165 ].…”

Section: Interventional Strategies To Correct Dysfunctional Mqc and D...mentioning

confidence: 99%

NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson’s Disease

Curtis

Seeds²,

Mattson

et al. 2022

Cells

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Dysfunctional mitochondrial quality control (MQC) is implicated in the pathogenesis of Parkinson’s disease (PD). The improper selection of mitochondria for mitophagy increases reactive oxygen species (ROS) levels and lowers ATP levels. The downstream effects include oxidative damage, failure to maintain proteostasis and ion gradients, and decreased NAD+ and NADPH levels, resulting in insufficient energy metabolism and neurotransmitter synthesis. A ketosis-based metabolic therapy that increases the levels of (R)-3-hydroxybutyrate (BHB) may reverse the dysfunctional MQC by partially replacing glucose as an energy source, by stimulating mitophagy, and by decreasing inflammation. Fasting can potentially raise cytoplasmic NADPH levels by increasing the mitochondrial export and cytoplasmic metabolism of ketone body-derived citrate that increases flux through isocitrate dehydrogenase 1 (IDH1). NADPH is an essential cofactor for nitric oxide synthase, and the nitric oxide synthesized can diffuse into the mitochondrial matrix and react with electron transport chain-synthesized superoxide to form peroxynitrite. Excessive superoxide and peroxynitrite production can cause the opening of the mitochondrial permeability transition pore (mPTP) to depolarize the mitochondria and activate PINK1-dependent mitophagy. Both fasting and exercise increase ketogenesis and increase the cellular NAD+/NADH ratio, both of which are beneficial for neuronal metabolism. In addition, both fasting and exercise engage the adaptive cellular stress response signaling pathways that protect neurons against the oxidative and proteotoxic stress implicated in PD. Here, we discuss how intermittent fasting from the evening meal through to the next-day lunch together with morning exercise, when circadian NAD+/NADH is most oxidized, circadian NADP+/NADPH is most reduced, and circadian mitophagy gene expression is high, may slow the progression of PD.

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The CD38 glycohydrolase and the NAD sink: implications for pathological conditions

Cited by 36 publications

References 330 publications

Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations

Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations

Cancer treatment-induced NAD+ depletion in premature senescence and late cardiovascular complications

NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson’s Disease

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