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At least 1,081 records · Page 60
All sourcesNASA NTRSDOE OSTI
DOE OSTI2020

Hydrometeorological sensitivities of net ecosystem carbon dioxide and methane exchange of an Amazonian palm swamp peatland

Here, we report ecosystem-scale CO 2 and CH 4 flux observations for an Amazonian palm swamp peatland over a two-year period in relation to hydrometeorological forcings. Seasonal and short-term variations in hydrometeorological forcing had a strong effect on carbon dioxide and methane fluxes. High air temperature and vapor pressure deficit exerted an important limitation on photosynthesis during the dry season, while latent heat flux appeared to be insensitive to these climate drivers. Evidence from light-response analyses and flux partitioning support that photosynthetic activity was downregulated during dry conditions, while ecosystem respiration was either inhibited or enhanced depending on water table position. The cumulative net ecosystem carbon dioxide exchange indicated that the peatland was a significant carbon dioxide sink ranging from –465 (–279 to –651) g C m -2 y -1 in 2018 to –462 (–277 to –647) g C m -2 y -1 in 2019. The forest was a methane source of 22 (20 to 24) g C m -2 y -1 , similar in magnitude to other tropical peatlands and larger than boreal and arctic peatlands. Furthermore, the annual carbon budget of this Amazonian palm swamp peatland appears to be a major carbon sink under current hydrometeorological conditions, but evidence indicates that the sink strength is vulnerable to future climate change.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2020

Geospatial coherence of surface-atmosphere fluxes in the upper Great Lakes region

Surface-atmosphere fluxes are known to vary at multiple time scales, but uncertainty is high as to how fluxes change spatially within regions. With an increase in the number of eddy covariance towers, we are now able to examine the geospatial coherence of ecosystem fluxes, using time-series correlation. Eighteen sites from Michigan and Wisconsin were used in this study, ranging from 100 m to 600 km apart. Surface-atmosphere fluxes from a six-month period were used to quantify spatial coherence on a pair-wise basis. Using geospatial statistics, carbon and sensible heat (H) fluxes were found to be 95% correlated directly outside of their flux footprint and 56% correlated up to a distance of ~35 km. Latent (LE) and momentum (τ) fluxes were less correlated, 83% directly outside of their flux footprint and 40% at a distance of ~130 km albeit, at a much larger spatial distance than for the carbon and sensible heat fluxes. All fluxes showed strong spectral resonance at diel and seasonal timescales, with 1-, 2- and 3-month periods being common modes of variability among H, LE, and τ fluxes. Results based on Empirical Orthogonal Function show distinct transitions of net ecosystem exchange from fall to winter before photosynthesis or respiration while H and τ do not exhibit coherent trends. Here, this work demonstrates the potential of quantifying geospatial coherence of surface-atmosphere fluxes in the Midwestern United States, with the ability to predict fluxes beyond the spatial limit of a single flux tower footprint. Ultimately, expanding the flux measurements to larger scales would allow better spatial scaling of terrestrial surface-atmosphere fluxes between tower footprint and modeling or remote sensing scales.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2021

Quantifying carbon budget, crop yields and their responses to environmental variability using the ecosys model for U.S. Midwestern agroecosystems

As one of the major agricultural production areas in the world, the United States (U.S.) Midwest plays a vital role in the global food supply and agricultural ecosystem services. Although significant efforts have been made in modeling the carbon cycle dynamics over this area, large uncertainty still exists in the previous simulations in terms of reproducing individual components of the carbon cycle and their responses to environmental variability. Here we evaluated the performance of an advanced agroecosystem model, ecosys, in simulating carbon budgets over the U.S. Midwest, considering both the magnitude of carbon flux/yield and its response to environmental (climate and soil) variability. We conducted model simulations and evaluations at 7 cropland eddy-covariance sites as well as over 293 counties of Illinois, Indiana, and Iowa in the U.S. Midwest. The site-level simulations showed that ecosys captured both the magnitude and seasonal patterns of carbon fluxes (i.e., net ecosystem carbon exchange (NEE), ecosystem gross primary production (GPP), and ecosystem respiration (Reco)), leaf area index (LAI), and dynamic plant carbon allocation processes, with R2 equal to 0.92, 0.87, 0.87, and 0.78 for GPP, NEE, Reco, and LAI, respectively across all the sites compared with the observations. For regional scale simulations, ecosys reproduced the spatial distribution and interannual variability of corn and soybean yields with the constraints of observed yields and a new remotely sensed GPP product, with R2 of multi-year averaged simulated and observed yield equal 0.83 and 0.80 for corn and soybean, respectively. The simulated responses of carbon cycle dynamics to environmental variability were consistent with that from the empirical observations at both site and regional scales. Furthermore, our results demonstrated the applicability of ecosys in simulating the carbon cycle and soil carbon dynamics of the U.S. Midwestern agroecosystems under different climate and soil conditions.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2021

A micrometeorological flux perspective on brush management in a shrub-encroached Sonoran Desert grassland

Woody plant encroachment typically limits the forage productivity of managed rangelands and alters a panoply of semiarid ecosystem processes and services. Intervention strategies to reduce woody plant abundance, collectively termed “brush management”, often lack observations to quantify and interpret changes in ecosystem processes. Furthermore, comparative studies between treated and untreated areas should account for heterogeneity since plant composition, microclimate, topoedaphic factors, and historical land use can substantially vary over short distances in drylands. Here, in this work, we quantify ecosystem responses to brush management after a single aerial herbicide application on an 18 hectare shrub-encroached grassland (savanna) in southern Arizona, USA. We conducted a pre- and post-treatment comparison of a flux tower site in the treated area with that of a tower in a nearby control site. The comparison, spanning a seven year period, included: (1) ground, airborne, and satellite-based measurements of vegetation structure, and (2) eddy covariance measurements. The herbicide treatment defoliated the dominant shrub (velvet mesquite, Prosopis velutina) and led to a temporary reduction in summer greening, but full foliar recovery occurred within two years. Contrary to expectations, perennial grass cover decreased and bare soil cover increased on the treated site. Relative amounts of evapotranspiration were reduced, while carbon uptake increased during the 2 year post-treatment period at the treated site due to a higher water use efficiency in the following spring. During mesquite recovery, carbon uptake was enhanced by higher gross primary productivity and accompanied by a decrease in ecosystem respiration relative to the untreated site. Mesquite recovery was facilitated by access to deep soil water, carbohydrate reserves in rooting systems, and a lower competition from reduced perennial grass cover.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2022

Causality guided machine learning model on wetland CH 4 emissions across global wetlands

Wetland CH 4 emissions are among the most uncertain components of the global CH 4 budget. The complex nature of wetland CH 4 processes makes it challenging to identify causal relationships for improving our understanding and predictability of CH 4 emissions. In this study, we used the flux measurements of CH 4 from eddy covariance towers (30 sites from 4 wetlands types: bog, fen, marsh, and wet tundra) to construct a causality-constrained machine learning (ML) framework to explain the regulative factors and to capture CH 4 emissions at sub-seasonal scale. We found that soil temperature is the dominant factor for CH 4 emissions in all studied wetland types. Ecosystem respiration (CO 2 ) and gross primary productivity exert controls at bog, fen, and marsh sites with lagged responses of days to weeks. Integrating these asynchronous environmental and biological causal relationships in predictive models significantly improved model performance. More importantly, modeled CH 4 emissions differed by up to a factor of 4 under a +1°C warming scenario when causality constraints were considered. These results highlight the significant role of causality in modeling wetland CH 4 emissions especially under future warming conditions, while traditional data-driven ML models may reproduce observations for the wrong reasons. Our proposed causality-guided model could benefit predictive modeling, large-scale upscaling, data gap-filling, and surrogate modeling of wetland CH 4 emissions within earth system land models.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2023

Interannual variability of spring and summer monsoon growing season carbon exchange at a semiarid savanna over nearly two decades

Eddy covariance measurements of land-atmosphere energy, carbon, and water exchange now span multiple decades at some sites, supporting an improved understanding of flux interannual variability (IAV) and its ecophysiological and physical controls. Most eddy covariance IAV studies have focused on temperate forest ecosystems, where carbon fluxes are large and flux records are longest – but also where IAV is much lower than in dryland regions, which have been identified as an essential driver of the trend and variability in the global terrestrial carbon sink. In this study, we leveraged 19 years of continuous micrometeorological measurements at the AmeriFlux US-SRM mesquite savanna site in southern Arizona, USA to quantify the IAV, trends, and drivers of carbon fluxes during the distinct spring and summer growing seasons. We also assessed the ability of modern satellite and land surface models to capture the IAV of seasonal water and carbon fluxes. Annual net ecosystem production (NEP) was small and highly variable (23 +/- 64 gC m –2 yr –1 ). Precipitation and associated measures of water availability determined most of the variability in NEP, largely through their influence on annual and seasonal gross ecosystem productivity (GEP) as opposed to ecosystem respiration (ER). Root-zone soil moisture captured between 73% (spring) and 85% (summer) of GEP variability and between 73% (spring) and 58% (summer) of ER variability. Throughout the study period, soil moisture and greenness increased with associated increases in GEP, ER and NEP. These trends were strongly influenced by very productive and wet summer growing seasons during the last two years, which were characterized by abundant understory grass cover. Typically, less than half of the variability in growing season GEP and evapotranspiration was captured by satellite-based estimates and land surface model simulations with local site forcing and calibration, highlighting the ongoing utility of long-term datasets to support careful model testing and improvement.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2019

Cost minimization of deoxygenation for control of Vampirovibrio chlorellavorus in Chlorella sorokiniana cultures

Deoxygenation is a strategy for preventing Vampirovibrio chlorellavorus infection of Chlorella sorokiniana cultures. Deoxygenation cost was minimized by sparging with nitrogen gas for only one hour at the onset of night and relying on naturally-occurring dark-respiration to maintain low oxygen concentrations throughout the night. This technique substantially reduced V. chlorellavorus infection in laboratory co-cultures. The cost of the approach was evaluated in outdoor experiments with one pure water and one pathogen-free C. sorokiniana culture, grown in a 150-L sealed, vented, translucent-polyethylene reactor. Unlike the small laboratory reactors, which were also sealed and vented, the much larger outdoor reactor maintained the dissolved oxygen concentration in the C. sorokiniana culture at near zero concentration throughout the night cycle. This demonstrates that large covered tanks in commercial applications would keep oxygen concentration near zero for the entire night. The total nitrogen sparged, per night, per liter of algal culture, was determined for the 150-L reactor, and used to estimate the cost per m2 for large scale raceways. Onsite nitrogen generators are the most cost-effective method to supply a high flow of nitrogen gas to commercial scale raceways. The cost of deoxygenation treatment ranged from $16/ton AFDW algae for a shallow (2 cm) gravity flow system with 75% harvest prior to deoxygenation to over $1,300/ton for a 20 cm depth raceway with plastic tanks.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Development of a kinetic model to describe six types of symbiotic interactions in a formate utilizing microalgae-bacteria cultivation system

This study investigated an algae/formate-utilizing-bacteria system that has been developed for carbon capture. This photomixotrophic consortium consumed formate to support bacterial growth so that the resulting respiration CO 2 could be simultaneously used by algae to avoid CO 2 gas-lipid mass transfer limitation. To understand biomass growth and population interactions in this unique system, a kinetic model has been developed to describe algae and bacteria multiplication, formate and nitrogen utilizations, CO 2 mass transfer, O 2 generation and consumption, lighting condition and shading effect. The simulation indicated that this ecosystem could form six types of interactions (mutualism, commensalism, parasitism, neutralism, amensalism, and competition) depending on the light intensity and nutrient availability. Furthermore, the simulation of both batch culture and chemostat, along with parameter sensitivity tests and experimental observations, offered insights into optimal applications of algae-bacteria consortium based photobiorefinery.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Using mid-infrared spectroscopy to estimate soil microbial properties at the continental scale

Understanding microbial community properties is critical to improving the predictions of biogeochemical processes for enhancing soil carbon sequestration. Here, in this observational study, mid-infrared (MIR) spectroscopy and partial least squares regression was used to predict soil microbial and chemical properties from diverse ecosystems across the continental USA. Random calibration and validation demonstrated the prediction potential for soil properties using MIR spectra, with the strongest predictions for microbial respiration, followed by microbial biomass carbon and nitrogen, ß-glucosidase activity, as well as soil chemical properties including organic carbon and total nitrogen. Microbial properties were mainly positively correlated to spectral regions associated with aliphatic C-H groups and C=O stretches of polysaccharides and negatively correlated to quartz and silicate-associated regions. We conclude that MIR spectroscopy can characterize soil microbial functions and be useful for the improvement of continental-scale soil carbon modeling and prediction programs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2014

Mitochondrial tRNA cleavage by tRNA-targeting ribonuclease causes mitochondrial dysfunction observed in mitochondrial disease

Highlights: • MTS-tagged ribonuclease was translocated successfully to the mitochondrial matrix. • MTS-tagged ribonuclease cleaved mt tRNA and reduced COX activity. • Easy and reproducible method of inducing mt tRNA dysfunction. - Abstract: Mitochondrial DNA (mtDNA) is a genome possessed by mitochondria. Since reactive oxygen species (ROS) are generated during aerobic respiration in mitochondria, mtDNA is commonly exposed to the risk of DNA damage. Mitochondrial disease is caused by mitochondrial dysfunction, and mutations or deletions on mitochondrial tRNA (mt tRNA) genes are often observed in mtDNA of patients with the disease. Hence, the correlation between mt tRNA activity and mitochondrial dysfunction has been assessed. Then, cybrid cells, which are constructed by the fusion of an enucleated cell harboring altered mtDNA with a ρ{sup 0} cell, have long been used for the analysis due to difficulty in mtDNA manipulation. Here, we propose a new method that involves mt tRNA cleavage by a bacterial tRNA-specific ribonuclease. The ribonuclease tagged with a mitochondrial-targeting sequence (MTS) was successfully translocated to the mitochondrial matrix. Additionally, mt tRNA cleavage, which resulted in the decrease of cytochrome c oxidase (COX) activity, was observed.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Aspirin increases mitochondrial fatty acid oxidation

The metabolic effects of salicylates are poorly understood. This study investigated the effects of aspirin on fatty acid oxidation. Aspirin increased mitochondrial long-chain fatty acid oxidation, but inhibited peroxisomal fatty acid oxidation, in two different cell lines. Aspirin increased mitochondrial protein acetylation and was found to be a stronger acetylating agent in vitro than acetyl-CoA. However, aspirin-induced acetylation did not alter the activity of fatty acid oxidation proteins, and knocking out the mitochondrial deacetylase SIRT3 did not affect the induction of long-chain fatty acid oxidation by aspirin. Aspirin did not change oxidation of medium-chain fatty acids, which can freely traverse the mitochondrial membrane. Together, these data indicate that aspirin does not directly alter mitochondrial matrix fatty acid oxidation enzymes, but most likely exerts its effects at the level of long-chain fatty acid transport into mitochondria. The drive on mitochondrial fatty acid oxidation may be a compensatory response to altered mitochondrial morphology and inhibited electron transport chain function, both of which were observed after 24 h incubation of cells with aspirin. These studies provide insight into the pathophysiology of Reye Syndrome, which is known to be triggered by aspirin ingestion in patients with fatty acid oxidation disorders. - Highlights: • Aspirin increases mitochondrial—but inhibits peroxisomal—fatty acid oxidation. • Aspirin acetylates mitochondrial proteins including fatty acid oxidation enzymes. • SIRT3 does not influence the effect of aspirin on fatty acid oxidation. • Increased fatty acid oxidation is likely due to altered mitochondrial morphology and respiration.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Anthelminthic drug niclosamide sensitizes the responsiveness of cervical cancer cells to paclitaxel via oxidative stress-mediated mTOR inhibition

Drug repurposing represents an alternative therapeutic strategy to cancer treatment. The potent anti-cancer activities of a FDA-approved anthelminthic drug niclosamide have been demonstrated in various cancers. However, whether niclosamide is active against cervical cancer is unknown. In this study, we investigated the effects of niclosamide alone and its combination with paclitaxel in cervical cancer in vitro and in vivo. We found that niclosamide significantly inhibited proliferation and induced apoptosis of a panel of cervical cancer cell lines, regardless of their cellular origin and genetic pattern. Niclosamide also inhibited tumor growth in cervical cancer xenograft mouse model. Importantly, niclosamide significantly enhanced the responsiveness of cervical cancer cell to paclitaxel. We further found that niclosamide induced mitochondrial dysfunctions via inhibiting mitochondrial respiration, complex I activity and ATP generation, which led to oxidative stress. ROS scavenge agent N-acetyl-L-cysteine (NAC) completely reversed the effects of niclosamide in increasing cellular ROS, inhibiting proliferation and inducing apoptosis, suggesting that oxidative stress induction is the mechanism of action of niclosamide in cervical cancer cells. In addition, niclosamide significantly inhibited mammalian target of rapamycin (mTOR) signaling pathway in cervical cancer cells and its inhibitory effect on mTOR is modulated by oxidative stress. Our work suggests that niclosamide is a useful addition to the treatment armamentarium for cervical cancer and induction of oxidative stress may be a potential therapeutic strategy in cervical cancer. - Highlights: • Niclosamide is active against cervical cancer cells in vitro and in vivo. • Niclosamide sensitizes cervical cancer cell response to paclitaxel. • Niclosamide induces mitochondrial dysfunction and oxidative damage. • Niclosamide inhibits mTOR signaling in an oxidative stress-dependent manner.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

The changes in glucose metabolism and cell proliferation in the kidneys of polycystic kidney disease mini-pig models

The pathogenic mechanism of polycystic kidney disease (PKD) is unclear. Abnormal glucose metabolism is maybe involved in hyper-proliferation of renal cyst epithelial cells. Mini-pigs are more similar to humans than rodents and therefore, are an ideal large animal model. In this study, for the first time, we systematically investigated the changes in glucose metabolism and cell proliferation signaling pathways in the kidney tissues of chronic progressive PKD mini-pig models created by knock-outing PKD1gene. The results showed that in the kidneys of PKD mini-pigs, the glycolysis is increased and the expressions of key oxidative phosphorylation enzymes Complexes I and IV significantly decreased. The activities of mitochondrial respiration chain Complexes I and IV significantly decreased; the phosphorylation level of key metabolism-modulating molecule AMP-activated protein kinase (AMPK) significantly decreased; and the mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK) signaling pathway are activated obviously. This study showed that in the kidneys of PKD mini-pigs, the level of glycolysis significantly increased, oxidative phosphorylation significantly decreased, and cell proliferation signaling pathways significantly activated, suggesting that metabolic changes in PKD may result in the occurrence and development of PKD through the activation of proliferation signaling pathways. - Highlights: • Mini-pigs are more similar to humans than rodents and are an ideal animal model. • The study was first performed in chronic model created by knock-outing PKD1gene. • We investigated the changes in glucose metabolism and cell proliferation. • The glycolysis was significantly increased in the kidneys of PKD mini-pigs. • The mTOR and ERK signaling pathway are activated obviously in PKD mini-pigs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Effect of sodium fluoride on the sperm mitochondrial DNA in mice

Previous studies demonstrated that fluoride, as a widespread environmental pollutant, induced the reproductive toxicity at high dose. Besides the decrease of sperm characteristics like concentration, survival, and sperm motility, it was found that high fluoride induced the destructive mitochondrial ultrastructure and decreased ATP production from mitochondrial respiration. However, whether fluoride exposure can damage the mitochondrial DNA (mtDNA) of sperm is still unknown. In this study, 100 male mice were randomly divided into four groups 25 each, which were administrated with the distilled water containing 0, 25, 50 and 100 mg L{sup −1} NaF, respectively for 60 days. After exposure, sperm mtDNA copy number was measured by real-time PCR, mtDNA integrity by acridine orange (AO) staining, and nuclear DNA (nDNA) integrity through long PCR amplification, as well as MTCYB and MTATP6 mutations by PCR and direct sequencing. The results showed that 100 mg L{sup −1} NaF significantly increased sperm mtDNA copy number, and reduced nDNA integrity. There were no changes observed in mtDNA integrity, and mutations of MTCYB and MTATP6 between fluoride groups and the control group. These results indicated that along with low sperm quality, sperm mtDNA copy number is also a sensitive biomarker to reflect the sperm toxicity of fluoride. - Highlights: • NaF significantly increased sperm mtDNA copy number, and reduced nDNA integrity. • NaF did not change sperm mtDNA integrity, and mutations of MTCYB and MTATP6. • Sperm mtDNA copy number can be a potential biomarker of fluoride-induced toxicity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Angiotensin-converting enzyme 2 regulates mitochondrial function in pancreatic β-cells

Highlights: • ACE2 improved glucose stimulated insulin secretion (GSIS) and mitochondrial membrane potential in INS-1 cells. • PCR array demonstrated that ACE2 up-regulated 67 mitochondria-related genes in INS-1 cells. • ACE2 deletion suppressed mitochondrial oxidation and calcium influx in islets. • ACE2 over-expression in db/db mice promoted mitochondrial oxidation and calcium influx in islets. Mitochondrial metabolism plays an essential role in the regulation of insulin release and glucose homeostasis. Evidence demonstrated that the angiotensin-converting enzyme 2 (ACE2) participates in the regulation of glucose metabolism, however, its role in mitochondrial metabolism remains unclear. The purpose of our study was to determine if ACE2 can regulate mitochondrial function in pancreatic β-cells. We found that ACE2 over-expression restored glucose-stimulated insulin secretion (GSIS) and mitochondrial membrane potential (MMP) in the presence of H{sub 2}O{sub 2} in INS-1 cells. PCR array demonstrated that ACE2 over-expression up-regulated 67 mitochondria-related genes in INS-1 cells. In pancreatic islets, ACE2 ablation attenuated intracellular calcium influx with a decrease in GSIS. Ace2{sup −/y} mice islets exhibited impaired mitochondrial respiration and lower production of ATP, along with decreased expression of genes involved in mitochondrial oxidation. In islets from db/db mice, ACE2 over-expression increased intracellular calcium influx and restored impaired mitochondrial oxidation, potentially causing an increase in GSIS. These results shed light on the potential roles of ACE2 in mitochondrial metabolism, moreover, may improve our understanding of diabetes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Mitochondrial tRNAThr 15909A>G mutation associated with hypertension in a Chinese Han pedigree

Highlights: • The m.15909A > G mutation abolishes a highly conserved base pairing 11U-24A in the D-stem of tRNA{sup Thr}. • The m.15909A > G mutation affects mitochondrial tRNA metabolism, translation and respiration. • The m.15909A > G mutation leads to the development of hypertension in this Chinese Han pedigree. Mitochondrial DNA mutations are one of the molecular genetic bases of hypertension. Here, we performed clinical, genetic and mutational evaluation, molecular characterization as well as biochemical analysis of a Chinese Han family with maternally inherited hypertension. The m.15909A > G variant in tRNA{sup Thr} was identified. This mutation abolished a highly conserved base pairing (11U-24A) in the D-stem of tRNA{sup Thr} and affected the structure and function of mitochondrial tRNA{sup Thr}. As a result, the overall levels of mitochondrial translation products was decreased. The reduced mitochondrial protein synthesis resulted in the decrease in the activity of complex, and in turn, the production of ATP decreased and the generation of ROS increased. The m.15909A > G mutation maybe an inherited factor leading to the development of hypertension in this Chinese Han pedigree.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Mersalyl prevents the Tl+-induced permeability transition pore opening in the inner membrane of Ca2+-loaded rat liver mitochondria

Highlights: • Interdependent participation of ANT and PiC is proposed in Tl{sup +}-induced pore opening. • Hydrophilic reagent mersalyl (MSL) till 5 μM inhibited opening the Tl{sup +}-induced pore. • The inhibiting effect of MSL was enhanced in experiments with N-ethylmaleimide. • The MSL inhibition of the pore opening was maximal in the presence of ADP and CsA. • Ability of ADP to inhibit the pore decreased in experiments with 20 μM MSL. It was earlier shown that the calcium load of rat liver mitochondria in medium containing TlNO{sub 3} and KNO{sub 3} resulted in the Tl{sup +}-induced mitochondrial permeability transition pore (MPTP) opening in the inner membrane. This opening was accompanied by an increase in swelling and membrane potential dissipation and a decrease in state 3, state 4, and 2,4-dinitrophenol-uncoupled respiration. This respiratory decrease was markedly leveled by mersalyl (MSL), the phosphate symporter (PiC) inhibitor which poorly stimulated the calcium-induced swelling, but further increased the potential dissipation. All of these effects of Ca{sup 2+} and MSL were visibly reduced in the presence of the MPTP inhibitors (ADP, N-ethylmaleimide, and cyclosporine A). High MSL concentrations attenuated the ability of ADP to inhibit the MPTP. Our data suggest that the PiC can participate in the Tl{sup +}-induced MPTP opening in the inner membrane of Ca{sup 2+}-loaded rat liver mitochondria.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Activation of TGR5 promotes mitochondrial biogenesis in human aortic endothelial cells

Highlights: • Activation of TGR5 increases the expression of PGC-1α, NRF1 and TFAM. • Activation of TGR5 promotes mitochondrial biogenesis. • Activation of TGR5 leads to a functional gain of mitochondria. • The effect of TGR5 on mitochondrial biogenesis is mediated by CREB. Impairment of mitochondrial biogenesis has been associated with vascular pathophysiology. The G-protein–coupled receptor (TGR5) is an important mediator of bile acid signaling and glucose metabolism. However, the effects of TGR5 on mitochondrial biogenesis in endothelial cells remain elusive. In this study, we found that activation of TGR5 using its specific agonist taurolithocholic acid (TLCA) promoted the expression of PGC-1α, a master regulator of mitochondrial biogenesis in human aortic endothelial cells (HAECs). Additionally, activation of TGR5 increased the expression of PGC-1α target genes, such as NRF1 and TFAM. Indeed, we found that TLCA treatment promoted mitochondrial biogenesis by increasing mitochondrial mass, mitochondrial-to-nuclear DNA (mtDNA/nDNA), COX-Ⅰ expression, and cytochrome c oxidase activity in HAECs. Notably, our results displayed that activation of TGR5 resulted in a functional gain in mitochondria by increasing the rate of respiration and ATP production. Mechanistically, we found that TLCA treatment activated the transcriptional factor CREB by inducing the phosphorylation of CREB at Ser133. Using the PKA/CREB inhibitor H89 abolished the effects of TLCA on PGC-1α, NRF1 and TFAM expression as well as the increase in mtDNA/nDNA and ATP production. These findings suggest that activation of TGR5 promoted mitochondrial biogenesis in endothelial cells, which is mediated by the CREB/PGC-1α signaling pathway.

60 APPLIED LIFE SCIENCES↗