bims-mignad 2025-06-15 papers

Issue of 2025–06–15
three papers selected by
Melisa Emel Ermert, Amsterdam UMC

Methods Mol Biol. 2025 ;2925 203-222

Metabolic Pathway Tracing for NAD+ Synthesis and Consumption.

NAD+ is an abundant cellular metabolite which plays vital roles in central metabolism while serving as a cofactor for oxidoreductases and cosubstrate for sirtuins and poly(ADP-ribose)polymerases (PARPs). Decreased tissue NAD+ levels have been linked to aging-associated metabolic decline and a host of chronic diseases. Cellular steady-state NAD+ levels are governed by contemporaneous synthetic and consumptive processes. Hence, lower NAD+ levels in aged tissues can arise from decreased synthesis or increased consumption. A static snapshot of the tissue levels of NAD+ is inadequate for assessing the highly dynamic pathway network which mediates NAD+ synthesis and consumption. Metabolic pathway tracing with stable isotope-labeled NAD+ precursors (e.g., nicotinamide (NAM), nicotinic acid (NA), tryptophan) and high-resolution mass spectrometry (HRMS) can unveil the individual contributions of synthesis and consumption to the steady-state NAD+ concentration. The metabolic fate of the NAD+ precursor can also be traced to metabolic products of NAD+ including NADH, NADP, and NADPH as well as intermediates in the various NAD+ biosynthetic pathways. Metabolic tracing of NAD+ synthesis and degradation as well as conversion of NAD+ to its downstream products is a highly versatile technique. It can be used to interrogate isolated cells, tissues slices, or specimens collected from preclinical or clinical in vivo studies (e.g., blood, urine, tissues). Bold claims about the pivotal role of NAD+ in human health and disease are typically fraught with uncertainty due to an incomplete understanding of NAD+ metabolism. Insight gleaned from metabolic pathway tracing can shed important new light on NAD+ metabolism and help to critically evaluate the intriguing link between cellular NAD+ levels and healthy aging.

Keywords: Mass isotopomer distribution profiling; Mass spectrometry; NAD+ consumption; NAD+ flux; NAD+ metabolism; NAD+ synthesis; Stable isotope tracing

DOI: https://doi.org/10.1007/978-1-0716-4534-5_14

Nutrients. 2025 May 29. pii: 1855. [Epub ahead of print]17(11):

Nicotinamide Adenine Dinucleotide Supplementation to Alleviate Heart Failure: A Mitochondrial Dysfunction Perspective.

Fan Yu, Huiying Zhao, Lu Luo, Wei Wu.

Heart failure represents the terminal stage in the development of many cardiovascular diseases, and its pathological mechanisms are closely related to disturbances in energy metabolism and mitochondrial dysfunction in cardiomyocytes. In recent years, nicotinamide adenine dinucleotide (NAD+), a core coenzyme involved in cellular energy metabolism and redox homeostasis, has been shown to potentially ameliorate heart failure through the regulation of mitochondrial function. This review systematically investigates four core mechanisms of mitochondrial dysfunction in heart failure: imbalance of mitochondrial dynamics, excessive accumulation of reactive oxygen species (ROS) leading to oxidative stress injury, dysfunction of mitochondrial autophagy, and disturbance of Ca2+ homeostasis. These abnormalities collectively exacerbate the progression of heart failure by disrupting ATP production and inducing apoptosis and myocardial fibrosis. NAD+ has been shown to regulate mitochondrial biosynthesis and antioxidant defences through the activation of the deacetylase family (e.g., silent information regulator 2 homolog 1 (SIRT1) and SIRT3) and to increase mitochondrial autophagy to remove damaged mitochondria, thus restoring energy metabolism and redox balance in cardiomyocytes. In addition, the inhibition of NAD+-degrading enzymes (e.g., poly ADP-ribose polymerase (PARP), cluster of differentiation 38 (CD38), and selective androgen receptor modulators (SARMs)) increases the tissue intracellular NAD+ content, and supplementation with NAD+ precursors (e.g., β-nicotinamide mononucleotide (NMN), nicotinamide riboside, etc.) also significantly elevates myocardial NAD+ levels to ameliorate heart failure. This study provides a theoretical basis for understanding the central role of NAD+ in mitochondrial homeostasis and for the development of targeted therapies for heart failure.

Keywords: ATP; heart failure; mitochondrial dysfunction; nicotinamide adenine dinucleotide; redox

DOI: https://doi.org/10.3390/nu17111855

Mol Cell. 2025 Jun 05. pii: S1097-2765(25)00461-7. [Epub ahead of print]

The NAMPT enzyme employs a switch that directly senses AMP/ATP and regulates cellular responses to energy stress.

Nicotinamide adenine dinucleotide (NAD+) is a crucial compound in energy metabolism and cell signaling. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme responsible for NAD+ biosynthesis from nicotinamide (NAM). Here, we report that NAMPT activity is inhibited by adenosine monophosphate (AMP) in response to energy stress. Our global metabolite-protein interaction mapping reveals that NAMPT differentially interacts with AMP from fasted mouse livers. Crystal structures of NAMPT-AMP show that AMP binds similarly to the NAMPT reaction product, nicotinamide mononucleotide (NMN). The inhibition of NAMPT by AMP can be relieved by NAMPT activators or adenosine triphosphate (ATP), likely in a competitive manner. Based on these findings, we further investigated upstream factors contributing to AMP accumulation and found that activation of purine synthesis unexpectedly promotes the rise of AMP during fasting. Notably, an increased AMP/ATP ratio correlates with NAD+ decline in ischemic stroke models, in which NAMPT activators can otherwise confer protection.

Keywords: AMP; ATP; NAD(+) biosynthesis; NAMPT; energy stress; fasting; ischemia; purine synthesis

DOI: https://doi.org/10.1016/j.molcel.2025.05.022