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Cellular Compartmentation and the Redox/Nonredox Functions of NAD.

ABSTRACT: Significance: Nicotinamide adenine dinucleotide (NAD+) spans diverse roles in biology, serving as both an important redox cofactor in metabolism and a substrate for signaling enzymes that regulate protein post-translational modifications (PTMs). Critical Issues: Although the interactions between these different roles of NAD+ (and its reduced form NADH) have been considered, little attention has been paid to the role of compartmentation in these processes. Specifically, the role of NAD+ in metabolism is compartment specific (e.g., mitochondrial vs. cytosolic), affording a very different redox landscape for PTM-modulating enzymes such as sirtuins and poly(ADP-ribose) polymerases in different cell compartments. In addition, the orders of magnitude differences in expression levels between NAD+-dependent enzymes are often not considered when assuming the effects of bulk changes in NAD+ levels on their relative activities. Recent Advances: In this review, we discuss the metabolic, nonmetabolic, redox, and enzyme substrate roles of cellular NAD+, and the recent discoveries regarding the interplay between these roles in different cell compartments. Future Directions: Therapeutic implications for the compartmentation and manipulation of NAD+ biology are discussed. Antioxid. Redox Signal. 31, 623-642.

SUBMITTER: Kulkarni CA

PROVIDER: S-EPMC6657305 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Cellular Compartmentation and the Redox/Nonredox Functions of NAD.

Kulkarni Chaitanya A CA Brookes Paul S PS

Antioxidants & redox signaling 20190326 9

Significance: Nicotinamide adenine dinucleotide (NAD+) spans diverse roles in biology, serving as both an important redox cofactor in metabolism and a substrate for signaling enzymes that regulate protein post-translational modifications (PTMs). Critical Issues: Although the interactions between these different roles of NAD+ (and its reduced form NADH) have been considered, little attention has been paid to the role of compartmentation in these p ...[more]

PMID: 30784294

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Project description:BackgroundDiabetes is a risk factor for heart failure and promotes cardiac dysfunction. Diabetic tissues are associated with nicotinamide adenine dinucleotide (NAD+) redox imbalance; however, the hypothesis that NAD+ redox imbalance causes diabetic cardiomyopathy has not been tested. This investigation used mouse models with altered NAD+ redox balance to test this hypothesis.MethodsDiabetic stress was induced in mice by streptozotocin. Cardiac function was measured by echocardiography. Heart and plasma samples were collected for biochemical, histological, and molecular analyses. Two mouse models with altered NAD+ redox states (1, Ndufs4 [NADH:ubiquinone oxidoreductase subunit S4] knockout, cKO, and 2, NAMPT [nicotinamide phosphoribosyltranferase] transgenic mice, NMAPT) were used.ResultsDiabetic stress caused cardiac dysfunction and lowered NAD+/NADH ratio (oxidized/reduced ratio of nicotinamide adenine dinucleotide) in wild-type mice. Mice with lowered cardiac NAD+/NADH ratio without baseline dysfunction, cKO mice, were challenged with chronic diabetic stress. NAD+ redox imbalance in cKO hearts exacerbated systolic (fractional shortening: 27.6% versus 36.9% at 4 weeks, male cohort P<0.05), and diastolic dysfunction (early-to-late ratio of peak diastolic velocity: 0.99 versus 1.20, P<0.05) of diabetic mice in both sexes. Collagen levels and transcripts of fibrosis and extracellular matrix-dependent pathways did not show changes in diabetic cKO hearts, suggesting that the exacerbated cardiac dysfunction was due to cardiomyocyte dysfunction. NAD+ redox imbalance promoted superoxide dismutase 2 acetylation, protein oxidation, troponin I S150 phosphorylation, and impaired energetics in diabetic cKO hearts. Importantly, elevation of cardiac NAD+ levels by NAMPT normalized NAD+ redox balance, alleviated cardiac dysfunction (fractional shortening: 40.2% versus 24.8% in cKO:NAMPT versus cKO, P<0.05; early-to-late ratio of peak diastolic velocity: 1.32 versus 1.04, P<0.05), and reversed pathogenic mechanisms in diabetic mice.ConclusionsOur results show that NAD+ redox imbalance to regulate acetylation and phosphorylation is a critical mediator of the progression of diabetic cardiomyopathy and suggest the therapeutic potential for diabetic cardiomyopathy by harnessing NAD+ metabolism.

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Cellular Compartmentation and the Redox/Nonredox Functions of NAD.

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Cellular Compartmentation and the Redox/Nonredox Functions of NAD<sup>.</sup>

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