Compartment-Specific Poly-ADP-Ribose Formation as a Biosensor for Subcellular NAD Pools

VanLinden, Magali R.; Niere, Marc; Aa, Nikiforov; Ziegler, Mathias; Dölle, Christian

doi:10.1007/978-1-4939-6993-7_4

Cited by 14 publications

(12 citation statements)

References 11 publications

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“…Several approaches have been developed to try to quantify NAD + availability in different subcellular compartments. Compartment-targeted expression of the catalytic domain of ADP-ribosyltransferase diphtheria toxin-like 1 (ARTD1, formerly called PARP1) has been used as a molecular detector of NAD + because formation of poly-ADP-ribose, which can be detected by immunofluorescence, functions as a proxy for NAD + availability [11,12]. In addition, NAD + metabolite tracing methods have been developed that quantify NAD + and NADH levels, and define how their ratios in different subcellular compartments under several stress conditions change [11,13,14,15].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, NAD + metabolite tracing methods have been developed that quantify NAD + and NADH levels, and define how their ratios in different subcellular compartments under several stress conditions change [11,13,14,15]. Free NAD + has been measured in almost all organelles, including the mitochondria, peroxisomes, the endoplasmic reticulum (ER), and the Golgi complex [11,12,13]. These measurements have revealed that steady state NAD + concentrations, as well as changes in NAD + concentrations in response to different stimuli, vary considerably between different subcellular compartments.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Glucose Metabolism by NAD+ and ADP-Ribosylation

Hopp

Grüter

Hottiger

2019

Cells

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Cells constantly adapt their metabolic pathways to meet their energy needs and respond to nutrient availability. During the last two decades, it has become increasingly clear that NAD+, a coenzyme in redox reactions, also mediates several ubiquitous cell signaling processes. Protein ADP-ribosylation is a post-translational modification that uses NAD+ as a substrate and is best known as part of the genotoxic stress response. However, there is increasing evidence that NAD+-dependent ADP-ribosylation regulates other cellular processes, including metabolic pathways. In this review, we will describe the compartmentalized regulation of NAD+ biosynthesis, consumption, and regeneration with a particular focus on the role of ADP-ribosylation in the regulation of glucose metabolism in different cellular compartments.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of Glucose Metabolism by NAD+ and ADP-Ribosylation

Hopp

Grüter

Hottiger

2019

Cells

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“…Several approaches have been attempted to visualize subcellular distribution of NAD + pools. For example, targeted expression of PARP-1 can be used as a molecular NAD + detector since the presence of NAD + can be visualized by the formation of immunodetectable poly-ADP-ribose (Dölle, Niere, Lohndal, & Ziegler, 2010;VanLinden, Niere, Nikiforov, Ziegler, & Dölle, 2017). Moreover, several genetically encoded NAD + biosensors have been developed, which contain a bipartite NAD + -binding domain derived from bacterial NAD + -dependent DNA ligase fused to a circularly permuted Venus fluorescent protein (cpVenus) (Cambronne et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…These NAD + biosensors can be expressed either in nucleus or in cytoplasm and exhibit reduction in their fluorescent signals upon binding to NAD + . With these powerful molecular tools, NAD + has been detected in the nucleus and almost all cytoplasmic organelles, including mitochondria, peroxisomes, endoplasmic reticulum (ER), and Golgi complex (Cambronne et al, 2016;Dölle et al, 2010;VanLinden et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Subcellular compartmentalization of NAD+ and its role in cancer: A sereNADe of metabolic melodies

Zhu

Liu

Park

et al. 2019

Pharmacology & Therapeutics

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Nicotinamide adenine dinucleotide (NAD +) is an essential biomolecule involved in many critical processes. Its role as both a driver of energy production and a signaling molecule underscores its importance in health and disease. NAD + signaling impacts multiple processes that are dysregulated in cancer, including DNA repair, cell proliferation, differentiation, redoxregulation, and oxidative stress. Distribution of NAD + is highly compartmentalized, with each subcellular NAD + pool differentially regulated and preferentially involved in distinct NAD +-dependent signaling or metabolic events. Emerging evidence suggests that targeting NAD + metabolism is likely to repress many specific mechanisms underlying tumor development and progression, including proliferation, survival, metabolic adaptations, invasive capabilities, heterotypic interactions with the tumor microenvironment, and stress response including notably DNA maintenance and repair. Here we provide a comprehensive overview of how compartmentalized NAD + metabolism in mitochondria, nucleus, cytosol, and extracellular space impacts cancer formation and progression, along with a discussion of the therapeutic potential of NAD +-targeting drugs in cancer.

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“…Besides the nucleus, cytosol and mitochondria, NAD + has also been detected in other subcellular compartments including the peroxisomes and the endoplasmic reticulum (ER) 52,53 .…”

Section: Introductionmentioning

confidence: 99%

Chronic depletion of subcellular NAD pools reveals their interconnectivity and a buffering function of mitochondria

VanLinden¹,

Høyland²,

Dietze³

et al. 2021

Preprint

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The coenzyme NAD is consumed by signaling enzymes including poly-ADP-ribose-polymerases (PARPs) and sirtuins. Understanding the mechanisms of aging-associated NAD decline and how cells cope with decreased NAD concentrations requires model systems reflecting chronic NAD deficiency. To evoke compartment-specific over-consumption of NAD, we have engineered cell lines expressing PARP activity in mitochondria, the cytosol, endoplasmic reticulum, or peroxisomes. Irrespective of the compartment targeted, total cellular NAD concentrations declined by ~40%. Isotope-tracer flux measurements and mathematical modeling showed that the lowered NAD concentration limits total NAD consumption kinetically. Moreover, NAD biosynthesis rate and capacity remained unchanged, thereby also precluding an increase of total NAD turnover. The chronic NAD deficiency was surprisingly well tolerated unless the mitochondria were targeted. Oxidative phosphorylation and glycolysis were little affected by NAD over-consumption in the other compartments. Likewise, peroxisomal NAD over-consumption was balanced by mitochondrial NAD decrease to maintain beta-oxidation of very long chain fatty acids in peroxisomes. We propose that subcellular NAD pools are interconnected, with mitochondria acting as a rheostat to facilitate NAD-dependent processes in organelles with excessive consumption.

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Compartment-Specific Poly-ADP-Ribose Formation as a Biosensor for Subcellular NAD Pools

Cited by 14 publications

References 11 publications

Regulation of Glucose Metabolism by NAD+ and ADP-Ribosylation

Regulation of Glucose Metabolism by NAD+ and ADP-Ribosylation

Subcellular compartmentalization of NAD+ and its role in cancer: A sereNADe of metabolic melodies

Chronic depletion of subcellular NAD pools reveals their interconnectivity and a buffering function of mitochondria

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