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Role of NAD+ and mitochondrial sirtuins in cardiac and renal diseases

Key Points

  • Nicotinamide adenine dinucleotide (NAD+) is a coenzyme with roles in several cardiac and renal metabolic processes

  • NAD+ depletion is emerging as a major contributor to the pathogenesis of cardiac and renal disease

  • Preclinical data suggest that NAD+ repletion strategies have the potential to restore healthy renal and cardiac metabolism and physiology

  • The mitochondrial sirtuins mediate some of the beneficial effects of NAD+ supplementation

  • NAD+ supplementation can directly enhance metabolism and improve cellular redox reactions in the setting of cardiac and renal disease

  • NAD+ is also a substrate for enzymes involved in DNA damage repair and calcium signalling pathways; NAD+ supplementation could alter these pathways to influence cell viability, organ function and disease outcomes

Abstract

The coenzyme nicotinamide adenine dinucleotide (NAD+) has key roles in the regulation of redox status and energy metabolism. NAD+ depletion is emerging as a major contributor to the pathogenesis of cardiac and renal diseases and NAD+ repletion strategies have shown therapeutic potential as a means to restore healthy metabolism and physiological function. The pleotropic roles of NAD+ enable several possible avenues by which repletion of this coenzyme could have therapeutic efficacy. In particular, NAD+ functions as a co-substrate in deacylation reactions carried out by the sirtuin family of enzymes. These NAD+-dependent deacylases control several aspects of metabolism and a wealth of data suggests that boosting sirtuin activity via NAD+ supplementation might be a promising therapy for cardiac and renal pathologies. This Review summarizes the role of NAD+ metabolism in the heart and kidney, and highlights the mitochondrial sirtuins as mediators of some of the beneficial effects of NAD+-boosting therapies in preclinical animal models. We surmise that modulating the NAD+–sirtuin axis is a clinically relevant approach to develop new therapies for cardiac and renal diseases.

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Figure 1: Cardiac and renal biosynthesis and the metabolome of nicotinamide adenine dinucleotide (NAD+).
Figure 2: The potential effects of nicotinamide adenine dinucleotide (NAD+) therapy on cardiac and renal pathophysiology.

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Acknowledgements

We acknowledge the scientists whose discoveries were the basis for this review, thank the anonymous peer-reviewers for helpful comments, and apologize to our colleagues whose work we could not cite. We acknowledge funding support from the American Heart Association grants 12SDG8840004 and 12IRG9010008, The Ellison Medical Foundation, Friedreich's Ataxia Research Alliance, the NIH and the NIA grant R01AG045351, the NIH and the NIAAA grant R01AA022146, the Duke Pepper Older Americans Independence Center (OAIC) Program in Ageing Research supported by the National Institute of Ageing (P30AG028716-01), the Duke O'Brien Center for Kidney Research (5P30DK096493-02). K.A.H. was supported by an NIH/NIGMS training grant to Duke University Pharmacological Sciences Training Program (5T32GM007105-40) and is supported by an NIH pre-doctoral fellowship 1F31HL127959. A.S.M. is supported by an NIH pre-doctoral fellowship 1F31HL123275-31.

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All authors researched the data, discussed the content, wrote the text and reviewed or edited the manuscript before submission.

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Correspondence to Matthew D. Hirschey.

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Glossary

Nicotinamide adenine dinucleotide

(NAD+). A pyridine dinucleotide and important metabolic cofactor.

ADPR cyclases

Effector molecules that generate calcium-mobilizing second messengers.

ADP ribosyltransferases

Enzymes that transfer the ADPR group of NAD+ as a signal to repair damaged DNA.

Sirtuins

NAD+-dependent protein deacylases that consume NAD+ to remove post-translational acyl modifications from proteins.

Biosynthetic precursors

The biosynthetic precursors of NAD+ are dietary vitamin B3 compounds, including nicotinic acid, nicotinamide, and nicotinamide riboside. These precursors are recycled from the diet and used by tissues to generate NAD+.

Nicotinamide phosphoribosyltransferase

(NAMPT). An enzyme that converts nicotinamide into NMN in the NAD+ salvage pathway.

Oxidative phosphorylation

(OXPHOS). The electron transport pathway that is used by cells to generate ATP.

Parthanatos

A form of programmed cell death that is induced by accumulation of poly(ADP)ribose and the nuclear translocation of apoptosis-inducing factor from mitochondria.

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Hershberger, K., Martin, A. & Hirschey, M. Role of NAD+ and mitochondrial sirtuins in cardiac and renal diseases. Nat Rev Nephrol 13, 213–225 (2017). https://doi.org/10.1038/nrneph.2017.5

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