NAD+ Metabolism and Diseases with Motor Dysfunction

Lundt, Samuel; Ding, Shinghua

doi:10.3390/genes12111776

Cited by 15 publications

(12 citation statements)

References 176 publications

(211 reference statements)

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“…Alternatively, the different metabolic phenotypes observed in brain and SPC under the same metabolic constraints can be the result of disparities in the expression or regulation of the components of the NAD + :NADH pathways and/or the shuttling of NAD + :NADH between mitochondria and the cytosol. In agreement, previous evidence has demonstrated that MNs are particularly sensitive to changes in NAD + :NADH ratio and that reductions in NAD + could be a common phenomenon in motor neuron disorders (Lundt and Ding, 2021;Obrador et al, 2021).…”

Section: (See Fig 4 Right Panels)supporting

confidence: 92%

Altered MAM function shifts mitochondrial metabolism in SOD1-mutant models of ALS

Larrea

Tamucci

Kabra

et al. 2022

Preprint

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Mitochondrial defects are a common hallmark of familial and sporadic forms of amyotrophic lateral sclerosis (ALS). However, the origin of these defects, including reduced pyruvate metabolism and reduced oxygen consumption, is poorly understood. These metabolic functions are regulated in specialized endoplasmic reticulum (ER) domains in close contact with mitochondria, called mitochondrial-associated ER membranes (MAM). Recently it has been shown that MAM domains are disrupted in ALS, but the connection between MAM dysregulation and mitochondrial defects in ALS cells remains unclear. Using human embryonic stem cell (ESC)-derived motor neurons (hMNs) and mouse models with ALS-pathogenic mutations in superoxide dismutase 1 (SOD1), we found that the glycolytic deficiency in ALS is a direct consequence of the progressive disruption of MAM structure and function that hinders the use of glucose-derived pyruvate as a mitochondrial fuel and triggers a shift in mitochondrial substrates from pyruvate to fatty acids. This glycolytic deficiency, over time, induces significant alterations in mitochondrial electron flow and in the active/dormant (A/D) status of complex I in spinal cord, but not in brain. These data agree with a role for MAM in the maintenance and regulation of cellular glucose metabolism and suggest that MAM disruption in ALS could be the underlying cause of the bioenergetic deficits observed in the disease.

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Section: (See Fig 4 Right Panels)supporting

confidence: 92%

Altered MAM function shifts mitochondrial metabolism in SOD1-mutant models of ALS

Larrea

Tamucci

Kabra

et al. 2022

Preprint

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“…also reported that NAD + supplementation could be utilized in a broad spectrum of NAD + deficiency‐related pathologies, such as cancer, infection, acute injury, metabolism‐related disorders, and neurodegenerative diseases. [ 50–52 ]…”

Section: Discussionmentioning

confidence: 99%

“…Xie et al also reported that NAD + supplementation could be utilized in a broad spectrum of NAD + deficiency-related pathologies, such as cancer, infection, acute injury, metabolism-related disorders, and neurodegenerative diseases. [50][51][52] Mitochondria, as energy plants, participate in signal transmission, cell differentiation, oxidative stress reactions, and calcium homeostasis. [53] Triphenylphosphonium cation (TPP + ) is the most adopted moiety that can easily and efficiently permeate the mitochondrial inner membrane.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial‐Targeting Vitamin B₃ Ameliorates the Phenotypes of Parkinson's Disease In Vitro and In Vivo by Restoring Mitochondrial Function

Xin

Yang

Ding

et al. 2022

Advanced Therapeutics

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Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by progressive dopaminergic neuron loss, which affects millions of people worldwide, especially elderly individuals. Mitochondrial dysfunction is believed to be one crucial causative factor of PD. Therefore, restoring mitochondrial function is highly recommended for the treatment of PD. Herein, it is found that vitamin B 3 (VB 3 ) protects the dopaminergic cell line SH-SY5Y against rotenone-induced apoptosis by restoring mitochondrial dysfunction. To further improve the efficacy, a derivative of VB 3 , mitochondrial-targeting VB 3 (Mito-VB 3 ), is developed. It is demonstrated that Mito-VB 3 rescues SH-SY5Y cells from the neurotoxicity of oxidative stress. More importantly, Mito-VB 3 ameliorates the phenotypes of the Drosophila PD model. Mechanistically, Mito-VB 3 enhances nicotinamide adenine dinucleotide (NAD + ) levels, reduces ROS generation, elevates ATP levels, and restores mitochondrial membrane potential. Meanwhile, Mito-VB 3 promotes mitochondrial biogenesis by activating the NAD + /SIRT1/PGC1𝜶 pathway. In summary, the results demonstrate that Mito-VB 3 displays remarkable neuroprotective effects in the cell and Drosophila PD models and that Mito-VB 3 might serve as a potential therapeutic candidate for the treatment of PD and other mitochondrial dysfunction-related diseases.

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“…Playing a key role in energy transduction and cell signal transduction, NAD+ can be transformed into NADP, NAADP and cADPR ( 4 , 5 ). Moreover, NAD+ degradation products, such as nicotinamide and N-methyl nicotinamide, have also been considered as key regulators of energy metabolism, epigenetics and disease status ( 6 – 8 ). NAD+ pathway metabolites can also serve as substrates for a group of diverse enzymes ( 9 , 10 ), including SARM1, ARTs, PARPs, CD38, sirtuins, and RNA polymerases, which were involved in several aspects of cellular homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Development of prognostic indicator based on NAD+ metabolism related genes in glioma

Chen

Wang

et al. 2023

Front. Surg.

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BackgroundStudies have shown that Nicotinamide adenine dinucleotide (NAD+) metabolism can promote the occurrence and development of glioma. However, the specific effects and mechanisms of NAD+ metabolism in glioma are unclear and there were no systematic researches about NAD+ metabolism related genes to predict the survival of patients with glioma.MethodsThe research was performed based on expression data of glioma cases in the Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. Firstly, TCGA-glioma cases were classified into different subtypes based on 49 NAD+ metabolism-related genes (NMRGs) by consensus clustering. NAD+ metabolism-related differentially expressed genes (NMR-DEGs) were gotten by intersecting the 49 NMRGs and differentially expressed genes (DEGs) between normal and glioma samples. Then a risk model was built by Cox analysis and the least shrinkage and selection operator (LASSO) regression analysis. The validity of the model was verified by survival curves and receiver operating characteristic (ROC) curves. In addition, independent prognostic analysis of the risk model was performed by Cox analysis. Then, we also identified different immune cells, HLA family genes and immune checkpoints between high and low risk groups. Finally, the functions of model genes at single-cell level were also explored.ResultsConsensus clustering classified glioma patients into two subtypes, and the overall survival (OS) of the two subtypes differed. A total of 11 NAD+ metabolism-related differentially expressed genes (NMR-DEGs) were screened by overlapping 5,995 differentially expressed genes (DEGs) and 49 NAD+ metabolism-related genes (NMRGs). Next, four model genes, PARP9, BST1, NMNAT2, and CD38, were obtained by Cox regression and least absolute shrinkage and selection operator (Lasso) regression analyses and to construct a risk model. The OS of high-risk group was lower. And the area under curves (AUCs) of Receiver operating characteristic (ROC) curves were >0.7 at 1, 3, and 5 years. Cox analysis showed that age, grade G3, grade G4, IDH status, ATRX status, BCR status, and risk Scores were reliable independent prognostic factors. In addition, three different immune cells, Mast cells activated, NK cells activated and B cells naive, 24 different HLA family genes, such as HLA-DPA1 and HLA-H, and 8 different immune checkpoints, such as ICOS, LAG3, and CD274, were found between the high and low risk groups. The model genes were significantly relevant with proliferation, cell differentiation, and apoptosis.ConclusionThe four genes, PARP9, BST1, NMNAT2, and CD38, might be important molecular biomarkers and therapeutic targets for glioma patients.

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NAD+ Metabolism and Diseases with Motor Dysfunction

Cited by 15 publications

References 176 publications

Altered MAM function shifts mitochondrial metabolism in SOD1-mutant models of ALS

Altered MAM function shifts mitochondrial metabolism in SOD1-mutant models of ALS

Mitochondrial‐Targeting Vitamin B₃ Ameliorates the Phenotypes of Parkinson's Disease In Vitro and In Vivo by Restoring Mitochondrial Function

Development of prognostic indicator based on NAD+ metabolism related genes in glioma

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NAD+ Metabolism and Diseases with Motor Dysfunction

Cited by 15 publications

References 176 publications

Altered MAM function shifts mitochondrial metabolism in SOD1-mutant models of ALS

Altered MAM function shifts mitochondrial metabolism in SOD1-mutant models of ALS

Mitochondrial‐Targeting Vitamin B3 Ameliorates the Phenotypes of Parkinson's Disease In Vitro and In Vivo by Restoring Mitochondrial Function

Development of prognostic indicator based on NAD+ metabolism related genes in glioma

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Mitochondrial‐Targeting Vitamin B₃ Ameliorates the Phenotypes of Parkinson's Disease In Vitro and In Vivo by Restoring Mitochondrial Function