Dataset Information

Increased demand for NAD⁺ relative to ATP drives aerobic glycolysis.

ABSTRACT: Aerobic glycolysis, or preferential fermentation of glucose-derived pyruvate to lactate despite available oxygen, is associated with proliferation across many organisms and conditions. To better understand that association, we examined the metabolic consequence of activating the pyruvate dehydrogenase complex (PDH) to increase pyruvate oxidation at the expense of fermentation. We find that increasing PDH activity impairs cell proliferation by reducing the NAD⁺/NADH ratio. This change in NAD⁺/NADH is caused by increased mitochondrial membrane potential that impairs mitochondrial electron transport and NAD⁺ regeneration. Uncoupling respiration from ATP synthesis or increasing ATP hydrolysis restores NAD⁺/NADH homeostasis and proliferation even when glucose oxidation is increased. These data suggest that when demand for NAD⁺ to support oxidation reactions exceeds the rate of ATP turnover in cells, NAD⁺ regeneration by mitochondrial respiration becomes constrained, promoting fermentation, despite available oxygen. This argues that cells engage in aerobic glycolysis when the demand for NAD⁺ is in excess of the demand for ATP.

SUBMITTER: Luengo A

PROVIDER: S-EPMC8315838 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Increased demand for NAD<sup>+</sup> relative to ATP drives aerobic glycolysis.

Luengo Alba A Li Zhaoqi Z Gui Dan Y DY Sullivan Lucas B LB Zagorulya Maria M Do Brian T BT Ferreira Raphael R Naamati Adi A Ali Ahmed A Lewis Caroline A CA Thomas Craig J CJ Spranger Stefani S Matheson Nicholas J NJ Vander Heiden Matthew G MG

Molecular cell 20201230 4

Aerobic glycolysis, or preferential fermentation of glucose-derived pyruvate to lactate despite available oxygen, is associated with proliferation across many organisms and conditions. To better understand that association, we examined the metabolic consequence of activating the pyruvate dehydrogenase complex (PDH) to increase pyruvate oxidation at the expense of fermentation. We find that increasing PDH activity impairs cell proliferation by reducing the NAD<sup>+</sup>/NADH ratio. This change ...[more]

PMID: 33382985

Similar Datasets

Project description:The goal of this study is to identify a signature of bioenergetic and functional markers in the muscles of individuals with Parkinson's disease (PD). Quantitative physiological properties of in vivo hand muscle (FDI, first dorsal interosseus) and leg muscle (TA, Tibialis Anterior) of older individuals with PD were compared to historical age/gender-matched controls (N = 30). Magnetic resonance spectroscopy and imaging (MRS) were used to assess in vivo mitochondrial and cell energetic dysfunction, including maximum mitochondrial ATP production (ATPmax), NAD concentrations linked to energy/stress pathways, and muscle size. Muscle function was measured via a single muscle fatigue test. TA ATPmax and NAD levels were significantly lower in the PD cohort compared to controls (ATPmax: 0.66 mM/s ± 0.03 vs. 0.76 ± 0.02; NAD: 0.75 mM ± 0.05 vs. 0.91 ± 0.04). Muscle endurance and specific force were also lower in both hand and leg muscles in the PD subjects. Exploratory analyses of mitochondrial markers and individual symptoms suggested that higher ATPmax was associated with a greater sense of motivation and engagement and less REM sleep behavior disorder (RBD). ATPmax was not associated with clinical severity or individual symptom(s), years since diagnosis, or quality of life. Results from this pilot study contribute to a growing body of evidence that PD is not a brain disease, but a systemic metabolic syndrome with disrupted cellular energetics and function in peripheral tissues. The significant impairment of both mitochondrial ATP production and resting metabolite levels in the TA muscles of the PD patients suggests that skeletal muscle mitochondrial function may be an important tool for mechanistic understanding and clinical application in PD patients. This study looked at individuals with mid-stage PD; future research should evaluate whether the observed metabolic perturbations in muscle dysfunction occur in the early stages of the disease and whether they have value as theragnostic biomarkers.

Project description:ObjectiveThe mitochondrial nicotinamide adenine dinucleotide (NAD) kinase (MNADK) mediates de novo mitochondrial NADP biosynthesis by catalyzing the phosphorylation of NAD to yield NADP. In this study, we investigated the function and mechanistic basis by which MNADK regulates metabolic homeostasis.MethodsGeneralized gene set analysis by aggregating human patient genomic databases, metabolic studies with genetically engineered animal models, mitochondrial bioenergetic analysis, as well as gain- and loss- of-function studies were performed to address the functions and mechanistic basis by which MNADK regulates energy metabolism and redox state associated with metabolic disease.ResultsHuman MNADK common gene variants or decreased expression of the gene are significantly associated with the occurrence of type-2 diabetes, non-alcoholic fatty liver disease (NAFLD), or hepatocellular carcinoma (HCC). Ablation of the MNADK gene in mice led to decreased fat oxidation, coincident with increased respiratory exchange ratio (RER) and decreased energy expenditure upon energy demand triggered by endurance exercise or fasting. On an atherogenic high-fat diet (HFD), MNADK-null mice exhibited hepatic insulin resistance and glucose intolerance, indicating a type-2 diabetes-like phenotype in the absence of MNADK. MNADK deficiency led to a decrease in mitochondrial NADP(H) but an increase in cellular reactive oxygen species (ROS) in mouse livers. Consistently, protein levels of the major metabolic regulators or enzymes were decreased, while their acetylation modifications were increased in the livers of MNADK-null mice. Feeding mice with a HFD caused S-nitrosylation (SNO) modification, a posttranslational modification that represses protein activities, on MNADK protein in the liver. Reconstitution of an SNO-resistant MNADK variant, MNADK-S193, into MNADK-null mice mitigated hepatic steatosis induced by HFD.ConclusionMNADK, the only known mammalian mitochondrial NAD kinase, plays important roles in preserving energy homeostasis to mitigate the risk of metabolic disorders.

Dataset Information

Increased demand for NAD⁺ relative to ATP drives aerobic glycolysis.

Publications

Increased demand for NAD<sup>+</sup> relative to ATP drives aerobic glycolysis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Increased demand for NAD+ relative to ATP drives aerobic glycolysis.

Publications

Increased demand for NAD<sup>+</sup> relative to ATP drives aerobic glycolysis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Increased demand for NAD⁺ relative to ATP drives aerobic glycolysis.