On February 17, 2024, the international journal Antioxidants & RedoxSignaling published a new blockbuster review on NADH. The review collects all the major data on NADH related to metabolism and cellular pathways, such as its coenzyme activity, its effects on cell death, and its role in regulating redox and calcium homeostasis; It also examines gene expression control, as well as the potential effects of NADH on neurodegenerative diseases, heart disease, and infections, and its application in clinical settings.
Figure 1NADH: Oxygen Reduction Sensor for Age-Related Diseases.
NADH: Energy Metabolism
NADH is a key reducing agent that plays a vital role in energy metabolism. It is produced mainly by the reduction of NAD+ and is consumed by self-oxidation when needed. NADH is produced and consumed in two main energy production pathways, glycolysis and oxidative phosphorylation, which occur in the cytoplasm and mitochondrial matrix, respectively.
As a cofactor in a variety of enzymatic reactions, NADH plays a vital role in cellular function. It acts as an electron carrier to transport high-energy electrons produced by metabolic reactions into the electron transport chain of mitochondria, especially in processes such as glycolysis and the tricarboxylic acid (TCA) cycle. In addition, NADH also acts as a cofactor for dehydrogenases in various biosynthetic pathways, including fatty acid synthesis. What's more, NADH also supports antioxidant defenses by participating in the reduction of glutathione, helping cells fight oxidative stress. This versatility highlights the importance of NADH in facilitating a variety of enzymatic reactions that are essential for energy production, metabolic regulation, and maintaining cellular redox homeostasis.
Figure 2NADH Participation Energy Generation: Schematic diagram of the Krebs cycle (TCA) and electron transmission chain (ETC) in mitochondria.
NADH: mitochondrial function
NADH is mainly found in mitochondria, along with flavin adenine dinucleotide, which is one of the important coenzymes that favor mitochondrial statusBecause it helps in generating ATP. In addition, NADH improves mitochondrial membrane potential due to its properties of inhibition of the outer mitochondrial membrane (MOM) VDAC (voltage-dependent anion channel). NADH interacts with VDAC, affects the permeability of channels, and participates in the regulation of mitochondrial functionAffects the flux of metabolites across the outer mitochondrial membrane, influencing processes such as oxidative phosphorylation and apoptosis.
Figure 3NADH** in the granularity contributes to the formation of ATP
NADH: Affects calcium homeostasis
NADH plays a crucial role in regulating calcium homeostasis, primarily by influencing intracellular Ca2+ channels, specifically the Ca2+ channel gated by inositol 1,4,5-triphosphate (IP3). Previous studies have noted that NADH is four times more potent than NAD+ in regulating IP3-gated Ca2+ channels, with a five-fold increase in effectivenessAnd at 50 mNADH, an increase in half of the IP3R calcium release occurs. In addition, NADH inhibits related receptors in the myocardium.
NADH: regulates gene expression
When NADH is not used as a substrate for ATP production, it is transported into the cytoplasm to regulate protein acetylation and gene expression. The mechanism by which NADH is responsible for regulating gene expression may involve other molecules involved in the transcriptional pathway. For example, both NAD+ and NADH directly affect the function of the co-repressor CTBP (carboxy-terminal binding protein), which binds to transcriptional repressors of cells and viruses, and its overall effect is to silence the expression of specific genes involved in development, cell cycle regulation, and transformation. Studies have shown that increased levels of NADH can stimulate CTBP to bind to its target, thereby improving CTBP-mediated transcriptional repression.
NADH: Reduces cell death
Since NAD+ and NADH are regulators of sirtuins, both molecules can be involved in inducing cell necrosis. A recent study highlighted the major histological changes observed after pretreatment of pancreatic islets with a unique intraperitoneal injection of NADH in a model of streptozotocin (STZ)-induced diabetes to assess the effect of NADH on pancreatic necrosis. At the histological level,NADH pretreatment showed reduced cell death, reduced necrosis, and favored apoptosis, with the aim of preventing inflammation from further damaging the cells.
Figure 4NADH can reduce cell death and protect cells.
NADH: Redox homeostasis
NADH is a potent antioxidant in both enzymatic and non-enzymatic reactions. Unlike other forms of nicotinamide nucleotide, NADH is in a reduced form and is hydrophilic, exhibiting the ability to inhibit lipid peroxidation. In an in vitro study, NADH demonstrated its ability to reduce oxidative stress by rescuing the human hepatocellular cell line Lo2 from damage by X-ray irradiation. In addition, NADH showed a protective effect by upregulating the expression of anti-apoptotic proteins and downregulating the expression of pro-apoptotic proteins. Another study found that NADH had a similar protective effect on doxorubicin-damaged DNA.
NADH: Nutrition and ketosis
Diet and food intake affect NADH levels and act as NADH regulators, influencing the NAD+ NADH ratio by alternating between increasing or decreasing their amounts. The ketogenic diet is a high-fat, low-carb diet designed to mimic the effects of calorie restriction, and one study has shown that it is not only an extremely effective method for medically refractory epilepsy, but also causes several metabolic changes. Several other studies have shown that:Ketones directly affect NADH levels by enhancing NADH oxidation in the electron transport chain (i.e., increasing the NAD+ NADH ratio), thereby inhibiting the increase in mitochondrial ROS production associated with excitotoxic damage.
NADH: Aging-related disease
Dysregulation of oxidative stress and NADH levels is thought to affect pathological pathways associated with various age-related diseases by promoting their primary markers. Studies have shown that the plasma NAD+ metabolome is dysregulated during the "normal" aging process. This observation suggests that the homeostasis of the NAD+ NADH pool plays a crucial role in a variety of cellular processes, including the senescence process. In a study of the effects of NADH on aging brains, it was also found that NADH had an enhanced effect on cognitive function in older rats. Other studies have highlighted age-related differences in NADH-dependent hypoxia responses, with a 36% increase in NADH levels in adult rats and a 10% increase in older rats.
Figure 5Effect of NADH on cognitive function in aged rats.
nadh: The effect shown in the app
Given its role in supporting mitochondrial function, NADH has been explored as a potential approach to mitochondrial dysfunction, such as certain neurodegenerative diseases. Studies have investigated the use of NADH supplements in diseases such as Parkinson's disease and Alzheimer's disease, which involve disruptions in cellular energy metabolism.
In addition, the antioxidant properties of NADH make it a candidate for anti-oxidative stress, a factor associated with aging and various pathological conditions. Emerging research has also suggested that NADH may also play a role in regulating sirtuin activity, influencing cellular processes related to longevity.
In addition to its potential role in **chondrial diseases, NADH has also shown promise in supporting cognitive function and reducing fatigue. Several studies have explored NADH supplementation as a means of increasing mental alertness and relieving symptoms such as chronic fatigue syndrome.
Numerous studies have shown that NADH may have beneficial effects on cholesterol levels and blood pressure. In two separate in vivo studies, rats supplemented with 5 mg of NADH daily for 8 weeks significantly reduced total cholesterol by about 30% and 10% in their respective studies. Various in vitro studies on cancer cells have shown that the addition of NADH significantly inhibits the growth of cancer cells.
Figure 6An overview of the role of NADH in different synthesis pathways such as ATP production, NAD+ cycle, L-dopamine production, and endocytoplasmic reticulum calcium release.
NADH: A vision for the future
The future prospects of utilizing NADH as a tool hold great promise in various fields of medicine. Ongoing research aims to elucidate the molecular mechanisms underlying the effects of NADH**, refine dosing, and explore its applicability in personalized medicine. In the future, NADH-based** will play a key role in promoting health and mitigating various disease states. However, comprehensive clinical trials and further exploration of the long-term effects of NADH will be necessary to determine its efficacy and safety, paving the way for its adoption as a tool for wider adoption in the medical arsenal.
References: 1]Schiuma G, Lara D, Clement J, Narducci M, Rizzo R nadh: the redox sensor in aging-related disorders. antioxid redox signal. 2024 feb 17.
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