Enhanced Adenosine Triphosphate Production Research Articles

274 Biotin Is required for the zinc homeostasis in the skin

Patients with biotin deficiency present symptoms that are similar to those in patients with acrodermatitis enteropathica (inherent zinc deficiency). However, the association between biotin and zinc deficiency remains unknown. We have previously shown that epidermal keratinocytes of mice fed zinc-deficient (ZD) diets secreted more adenosine triphosphate (ATP) than those of mice fed zinc-adequate (ZA) diets and that epidermal Langerhans cells are absent in ZD mice. Langerhans cells highly express CD39, which potently hydrolyzes ATP into adenosine monophosphate (AMP). Thus, a lack of Langerhans cells in ZD mice leads to non-hydrolysis ofATP, thereby leading to the development of ATP-mediated irritant contact dermatitis. In this study, we examined if biotin-deficient (BD) mice showed the same underlying mechanisms as those in ZD mice. BD mice showed reduced serum zinc levels, disappearance of epidermal Langerhans cells, and enhanced ATP production in the skin. Consequently, irritant contact dermatitis was significantly enhanced and prolonged in BD mice. In conclusion, the findings of our study showed that biotin deficiency leads to zinc deficiency because of which patients with biotin deficiency show similar symptoms as those with acrodermatitis enteropathica.

Biotin Is Required for the Zinc Homeostasis in the Skin.

Patients with biotin deficiency present symptoms that are similar to those in patients with acrodermatitis enteropathica (inherent zinc deficiency). However, the association between biotin and zinc deficiency remains unknown. We have previously shown that epidermal keratinocytes of mice fed zinc-deficient (ZD) diets secreted more adenosine triphosphate (ATP) than those of mice fed zinc-adequate (ZA) diets and that epidermal Langerhans cells are absent in ZD mice. Langerhans cells highly express CD39, which potently hydrolyzes ATP into adenosine monophosphate (AMP). Thus, a lack of Langerhans cells in ZD mice leads to non-hydrolysis of ATP, thereby leading to the development of ATP-mediated irritant contact dermatitis. In this study, we examined if biotin-deficient (BD) mice showed the same underlying mechanisms as those in ZD mice. BD mice showed reduced serum zinc levels, disappearance of epidermal Langerhans cells, and enhanced ATP production in the skin. Consequently, irritant contact dermatitis was significantly enhanced and prolonged in BD mice. In conclusion, the findings of our study showed that biotin deficiency leads to zinc deficiency because of which patients with biotin deficiency show similar symptoms as those with acrodermatitis enteropathica.

Enhancing hydrogen‐dependent growth of and carbon dioxide fixation by Clostridium ljungdahlii through nitrate supplementation

Synthesis gas (syngas) fermentation via the Wood-Ljungdahl pathway is receiving growing attention as a possible platform for the fixation of and renewable production of fuels and chemicals. However, the pathway operates near the thermodynamic limit of life, resulting in minimal adenosine triphosphate (ATP) production and long doubling times. This calls into question the feasibility of producing high-energy compounds at industrially relevant levels. In this study, we investigated the possibility of co-utilizing nitrate as an inexpensive additional electron acceptor to enhance ATP production during -dependent growth of Clostridium ljungdahlii, Moorella thermoacetica, and Acetobacterium woodii. In contrast to other acetogens tested, growth rate and final biomass titer were improved for C. ljungdahlii growing on a mixture of and when supplemented with nitrate. Transcriptomic analysis, labeling, and an electron balance were used to understand how electron flux was partitioned between and nitrate. We further show that, with nitrate supplementation, the ATP/adenosine diphosphate (ADP) ratio and acetyl-CoA pools were increased by fivefold and threefold, respectively, suggesting that this strategy could be useful for the production of ATP-intensive heterologous products from acetyl-CoA. Finally, we propose a pathway for enhanced ATP production from nitrate and use this as a basis to calculate theoretical yields for a variety of products. This study demonstrates a viable strategy for the decoupling of ATP production from carbon dioxide fixation, which will serve to significantly improve the fixation rate and the production metrics of other chemicals from and in this host.

USMG5 Ashkenazi Jewish founder mutation impairs mitochondrial complex V dimerization and ATP synthesis.

Leigh syndrome is a frequent, heterogeneous pediatric presentation of mitochondrial oxidative phosphorylation (OXPHOS) disease, manifesting with psychomotor retardation and necrotizing lesions in brain deep gray matter. OXPHOS occurs at the inner mitochondrial membrane through the integrated activity of five protein complexes, of which complex V (CV) functions in a dimeric form to directly generate adenosine triphosphate (ATP). Mutations in several different structural CV subunits cause Leigh syndrome; however, dimerization defects have not been associated with human disease. We report four Leigh syndrome subjects from three unrelated Ashkenazi Jewish families harboring a homozygous splice-site mutation (c.87 + 1G>C) in a novel CV subunit disease gene, USMG5. The Ashkenazi population allele frequency is 0.57%. This mutation produces two USMG5 transcripts, wild-type and lacking exon 3. Fibroblasts from two Leigh syndrome probands had reduced wild-type USMG5 mRNA expression and undetectable protein. The mutation did not alter monomeric CV expression, but reduced both CV dimer expression and ATP synthesis rate. Rescue with wild-type USMG5 cDNA in proband fibroblasts restored USMG5 protein, increased CV dimerization and enhanced ATP production rate. These data demonstrate that a recurrent USMG5 splice-site founder mutation in the Ashkenazi Jewish population causes autosomal recessive Leigh syndrome by reduction of CV dimerization and ATP synthesis.

Treatment with D-β-hydroxybutyrate protects heart from ischemia/reperfusion injury in mice

The present study was designed to examine the protection of D-β-hydroxybutyrate (BHB) against ischemia/reperfusion (I/R) injury in heart and investigate its underlying mechanism. Male adult mice were exposed to 30 min of ischemia and 24 h of reperfusion. Osmotic pumps were implanted subcutaneously 5 min before reperfusion for continuous delivery of the exogenous BHB (1.6 mmol/kg/24 h). Treatment with BHB reduced infarct size and levels of cardiac troponin I, creatine kinase and lactate dehydrogenase in serum, attenuated apoptosis in myocardium, and preserved cardiac function of I/R mice. Importantly, treatment of I/R mice with BHB promoted autophagic flux, evidenced by reduced the ratio of LC3-II/LC3-I and protein expression of p62 and enhanced protein expression of lysosome associated membrane protein-2 (Lamp2) in myocardium. Treatment of I/R mice with BHB reduced mitochondrial formation of reactive oxygen species, enhanced adenosine triphosphate production, attenuated mitochondrial swelling, and partly restored mitochondrial membrane potential in myocardium. Furthermore, treatment of I/R mice with BHB abated oxidative stress and attenuated endoplasmic reticulum stress in myocardium. Our results indicated that treatment with exogenous BHB protected heart from I/R injury in mice.

Chlorogenic acid ameliorates endotoxin-induced liver injury by promoting mitochondrial oxidative phosphorylation

Acute or chronic hepatic injury is a common pathology worldwide. Mitochondrial dysfunction and the depletion of adenosine triphosphate (ATP) play important roles in liver injury. Chlorogenic acids (CGA) are some of the most abundant phenolic acids in human diet. This study was designed to test the hypothesis that CGA may protect against chronic lipopolysaccharide (LPS)-induced liver injury by modulating mitochondrial energy generation. CGA decreased the activities of serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. The contents of ATP and adenosine monophosphate (AMP), as well as the ratio of AMP/ATP, were increased after CGA supplementation. The activities of enzymes that are involved in glycolysis were reduced, while those of enzymes involved in oxidative phosphorylation were increased. Moreover, phosphorylated AMP-activated protein kinase (AMPK), and mRNA levels of AMPK-α, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), nuclear respiratory factor 1, and mitochondrial DNA transcription factor A were increased after CGA supplementation. Collectively, these findings suggest that the hepatoprotective effect of CGA might be associated with enhanced ATP production, the stimulation of mitochondrial oxidative phosphorylation and the inhibition of glycolysis.

Prostacyclin improves glucose utilization in patients with sepsis

Purpose: In patients with sepsis, impaired glucose metabolism and altered microcirculatory blood flow are common findings. Prostacyclin (PGI 2) improves tissue oxygenation, indicated by enhanced oxygen delivery (Do 2) and oxygen uptake (Vo2). The purpose of this study was to explore whether these effects are associated with improved glucose utilization. Methods: In 7 patients with sepsis, glucose metabolism was analyzed using dideuterated and 13C-labeled glucose and isotope dilution mass spectrometry. All patients received total parenteral nutrition with glucose covering 60% to 70% of the predicted energy expenditure and needed continuous intravenous insulin (40 μU · kg −1 · min −1) to keep blood glucose concentrations below 10 mmol · l −1. Vo2 and carbon dioxide production (Vco2) were continuously measured directly from the respiratory gases via indirect calorimetry. After equilibration of the infused labeled glucose with body glucose pool, baseline variables of glucose metabolism were assessed: glucose oxidation rate was determined from the enrichment of 13CO 2 in the expired gas during primed constant infusion of [U- 13C]glucose, glucose turnover rate (R a) from the plasma enrichment of simultaneously infused [6,6 2H 2]glucose. Endogenous glucose production rate was calculated as the difference between R a and glucose infusion rate. Then, we examined the effect of PGI 2 infusion (5 to 12.5 ng · kg −1 · min −1) on glucose metabolism and gaseous exchange. Results: The PGI 2-induced increase in DO 2 (from 15.8 to 17.7 ml · kg −1 - min −1; P < .05) resulted in an increase in directly measured Vo 2 from 5.0 to 5.3 ml · kg −1 min −1 ( P < .01) whereas Vco 2 remained unchanged. Although glucose turnover and production rates remained constant, glucose oxidation rate increased significantly from 1.21 to 1.38 mg · kg −1 · min −1 ( P < .02). Conclusions: Improving tissue perfusion and oxygenation with PGI 2 may also modify the impaired glucose metabolism by increasing glucose oxidation rate in patients with sepsis, suggesting enhanced adenosine triphosphate production.

Reduced human lymphocyte blastogenesis and enhancement of adenosine triphosphate (ATP) by L-carnitine.

Carnitine is associated with lipid synthesis and its deficiency may lead to cardiomegaly with parenchymal lipid in the heart, kidney and liver. In our study we found that pretreatment of peripheral blood mononuclear cells (PBMC) with serial dilutions of L-Carnitine (100 micrograms/ml-1 pg/ml) inhibits, in a dose-dependent manner, lymphocyte DNA synthesis stimulated with PHA (20 micrograms/ml). L-Carnitine did not have any effect on resting PBMC. The maximum inhibition was found at 10 micrograms/ml of L-Carnitine. Moreover, in a time-course study and using an enzymatic analysis (ATP monitoring reagent), L-Carnitine enhanced ATP production on PBMC treated and untreated with PHA, reaching a maximum effect at 30 min incubation. In another set of experiments PBMC were treated with L-Carnitine alone and in combination with PHA, and the percent of receptors CD3, CD4, and CD8 were calculated with flow cytometry. After the cell incubation with L-Carnitine, the percent of all receptors studied did not change compared to L-Carnitine-untreated cells (controls). These data suggest that L-Carnitine inhibits, in a dose-dependent manner, lymphocyte blastogenesis induced by PHA, probably through the enhancement of ATP synthesis, which is considered an inhibitor of phospholipase C activity and a suppressor in lymphocyte cultures.

Role of ATP in the maintenance of action potential configuration of the isolated working rat heart.

The relation between action potential configuration and myocardial adenosine triphosphate (ATP) concentration was analysed in isolated low and high work rat heart preparations. Glucose used as sole substrate could not provide total energy production when the isolated hearts performed high work. This may explain the decrease in action potential duration and plateau amplitude (phases 2 and 3) that occurred concomitantly with a low total myocardial ATP concentration. When atrial perfusion was changed to the retrograde mode, however, the action potential configuration was restored without an increase in the global myocardial ATP concentration. Pyruvate used as substrate instead of glucose enhanced ATP production by mitochondrial oxidation and partly restored the action potential modifications (principally phase 2). Adenosine added to glucose in the perfusate or infused in situ (before heart isolation and perfusion) enhanced ATP production by the adenine nucleotide salvage pathway and provided a protective effect for phase 2 and 3 action potential variables. The results using glucose as perfusate showed that there was no correlation between global ATP concentration and myocardial electrical activity. An analysis of the other results suggests that the primary problem in the working heart preparation is that the myocardium is in a state of relative hypoxia or ischaemia and that adenosine merely acts as a coronary vasodilator to improve myocardial oxygen delivery.