scholarly journals Cytoplasmic and Mitochondrial NADPH-Coupled Redox Systems in the Regulation of Aging

Nutrients ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 504 ◽  
Author(s):  
Patrick Bradshaw
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
Aging Process ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Thioredoxin Reductase ◽  
Nicotinamide Adenine ◽  
Model Organisms ◽  
Reduced Form ◽  
Redox Systems ◽  
Redox Stress ◽  
Species Longevity

The reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) protects against redox stress by providing reducing equivalents to antioxidants such as glutathione and thioredoxin. NADPH levels decline with aging in several tissues, but whether this is a major driving force for the aging process has not been well established. Global or neural overexpression of several cytoplasmic enzymes that synthesize NADPH have been shown to extend lifespan in model organisms such as Drosophila suggesting a positive relationship between cytoplasmic NADPH levels and longevity. Mitochondrial NADPH plays an important role in the protection against redox stress and cell death and mitochondrial NADPH-utilizing thioredoxin reductase 2 levels correlate with species longevity in cells from rodents and primates. Mitochondrial NADPH shuttles allow for some NADPH flux between the cytoplasm and mitochondria. Since a decline of nicotinamide adenine dinucleotide (NAD+) is linked with aging and because NADP+ is exclusively synthesized from NAD+ by cytoplasmic and mitochondrial NAD+ kinases, a decline in the cytoplasmic or mitochondrial NADPH pool may also contribute to the aging process. Therefore pro-longevity therapies should aim to maintain the levels of both NAD+ and NADPH in aging tissues.

Functional coupling of FcγRI to nicotinamide adenine dinucleotide phosphate (reduced form) oxidative burst and immune complex trafficking requires the activation of phospholipase D1

Blood ◽  
2001 ◽  
Vol 98 (12) ◽  
pp. 3421-3428 ◽  
Author(s):  
Alirio J. Melendez ◽  
Luce Bruetschy ◽  
R. Andres Floto ◽  
Margaret M. Harnett ◽  
Janet M. Allen
Keyword(s):  
Nadph Oxidase ◽  
Immune Complexes ◽  
Nicotinamide Adenine Dinucleotide ◽  
Intracellular Signaling ◽  
Antisense Oligonucleotides ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Sphingosine Kinase ◽  
Calcium Transients ◽  
Nicotinamide Adenine ◽  
Reduced Form

Abstract Immunoglobulin G (IgG) receptors (FcγRs) on myeloid cells are responsible for the internalization of immune complexes. Activation of the oxidase burst is an important component of the integrated cellular response mediated by Fc receptors. Previous work has demonstrated that, in interferon-γ–primed U937 cells, the high-affinity receptor for IgG, FcγRI, is coupled to a novel intracellular signaling pathway that involves the sequential activation of phospholipase D (PLD), sphingosine kinase, and calcium transients. Here, it is shown that both known PLD isozymes, PLD1 and PLD2, were present in these cells. With the use of antisense oligonucleotides to specifically reduce the expression of either isozyme, PLD1, but not PLD2, was found to be coupled to FcγRI activation and be required to mediate receptor activation of sphingosine kinase and calcium transients. In addition, coupling of FcγRI to activation of the nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) oxidase burst was inhibited by pretreating cells with 0.3% butan-1-ol, indicating an absolute requirement for PLD. Furthermore, use of antisense oligonucleotides to reduce expression of PLD1 or PLD2 demonstrated that PLD1 is required to couple FcγRI to the activation of NADPH oxidase and trafficking of internalized immune complexes for degradation. These studies demonstrate the critical role of PLD1 in the intracellular signaling cascades initiated by FcγRI and its functional role in coordinating the response to antigen-antibody complexes.

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