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Metabolic Alterations in NADSYN1-Deficient Cells
Nils W F Meijer1, Johan Gerrits1, Susan Zwakenberg2
1Department of Genetics, Section Metabolic Diagnostics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands.
Metabolites
|December 22, 2023
Summary
NAD synthetase 1 (NADSYN1) deficiency impairs nicotinamide adenine dinucleotide (NAD+) biosynthesis, causing significant metabolic changes. This study reveals how NADSYN1 deficiency impacts key cellular pathways even with alternative NAD+ precursors.
Area of Science:
- Biochemistry
- Metabolomics
- Genetics
Background:
- NAD synthetase 1 (NADSYN1) is crucial for nicotinamide adenine dinucleotide (NAD+) biosynthesis.
- NADSYN1 deficiency is recognized as a cause of congenital NAD+ deficiency disorders.
- Understanding the metabolic impact of NADSYN1 deficiency is essential for clinical insights.
Purpose of the Study:
- To investigate the metabolic consequences of NADSYN1 deficiency.
- To profile the metabolome in NADSYN1-deficient cells under varying NAD+ precursor conditions.
- To elucidate the impact on glycolysis, TCA cycle, pentose phosphate, and polyol pathways.
Main Methods:
- Gene disruption of NADSYN1 in A549 and HEK293T cell lines.
- Metabolome profiling using various NAD+ precursors (tryptophan, nicotinamide, nicotinic acid).
- Comparative analysis of metabolite alterations in deficient versus wild-type cells.
Main Results:
- NADSYN1 deficiency leads to decreased intracellular NAD+ levels, especially when nicotinamide is limited.
- Significant alterations in 122 metabolites (A549) and 69 metabolites (HEK293T) were observed.
- Metabolic phenotype includes dysregulation of glycolysis, TCA cycle, pentose phosphate pathway, and polyol pathway.
Conclusions:
- NADSYN1 deficiency profoundly impacts cellular metabolism beyond just NAD+ levels.
- The study highlights the critical role of NADSYN1 in maintaining metabolic homeostasis.
- Findings provide a foundation for understanding the pathophysiology of NADSYN1-related disorders.
