Brain NAD Is Associated With ATP Energy Production and Membrane Phospholipid Turnover in Humans.

Bernard Cuenoud,Stephen C Cunnane,Maurice Beaumont,Maya Shevlyakova,Lijing Xin,Rolf Gruetter,Özlem Ipek

doi:10.3389/fnagi.2020.609517

Abstract

The brain requires a large amount of energy, mostly derived from the metabolism of glucose, which decreases substantially with age and neurological diseases. While mounting evidence in model organisms illustrates the central role of brain nicotinamide adenine dinucleotide (NAD) for maintaining energy homeostasis, similar data are sparse in humans. This study explores the correlations between brain NAD, energy production and membrane phospholipid metabolism by 31-phosphorous magnetic resonance spectroscopy (31P-MRS) across 50 healthy participants including a young (mean age 27.1-year-old) and middle-aged (mean age 56.4-year-old) group. The analysis revealed that brain NAD level and NAD+/NADH redox ratio were positively associated with ATP level and the rate of energy production, respectively. Moreover, a metabolic network linking NAD with membrane phospholipid metabolism, energy production, and aging was identified. An inverted trend between age and NAD level was detected. These results pave the way for the use of 31P-MRS as a powerful non-invasive tool to support the development of new therapeutic interventions targeting NAD associated phospho-metabolic pathways in brain aging and neurological diseases.

Highlights

Nicotinamide adenine dinucleotide (NAD) is a vital cofactor involved in brain bioenergetics for metabolism and adenosine triphosphate (ATP) production, the energy currency of the brain (Lautrup et al, 2019)
Representative 31P MR spectra acquired for the occipital lobe of a young and a middle-age subject exhibited excellent spectral resolution at 7 Tesla that allowed the detection of 13 resonances including separate detection of nicotinamide adenine dinucleotide (NAD)+, NADH, GPE, GPC, PE and PC (Figure 1)
The key findings of our study revealed that brain NAD+ and tNAD levels were positively associated with brain ATP level

Summary

Introduction

Nicotinamide adenine dinucleotide (NAD) is a vital cofactor involved in brain bioenergetics for metabolism and ATP production, the energy currency of the brain (Lautrup et al, 2019). NAD+ plays an essential role in glycolysis and the citric acid (TCA) cycle, by its ability to accept hydride equivalents, forming NADH during adenosine triphosphate (ATP) production. NADH is one of the central electron donors in oxidative phosphorylation in the mitochondria, providing electrons to the electron transport chain (ETC) to generate most of the ATP. These reactions support the high energy demands of the brain, neurons, which are derived mostly from glucose metabolism under physiological conditions (Dienel, 2019). NAD+ is a key substrate for multiple NAD+-dependent enzymes implicated in neuronal integrity.

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