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• Puigserver 1998 Cell  + (Adaptive thermogenesis is an important com … Adaptive thermogenesis is an important component of energy homeostasis and a metabolic defense against obesity. We have cloned a novel transcriptional coactivator of nuclear receptors, termed PGC-1, from a brown fat cDNA library. PGC-1 mRNA expression is dramatically elevated upon cold exposure of mice in both brown fat and skeletal muscle, key thermogenic tissues. PGC-1 greatly increases the transcriptional activity of PPARgamma and the thyroid hormone receptor on the uncoupling protein (UCP-1) promoter. Ectopic expression of PGC-1 in white adipose cells activates expression of UCP-1 and key mitochondrial enzymes of the respiratory chain, and increases the cellular content of mitochondrial DNA. These results indicate that PGC-1 plays a key role in linking nuclear receptors to the transcriptional program of adaptive thermogenesis.ptional program of adaptive thermogenesis.)
• Ransy 2020 Int J Mol Sci  + (Addition of hydrogen peroxide (H<sub> … Addition of hydrogen peroxide (H₂O₂) is a method commonly used to trigger cellular oxidative stress. However, the doses used (often hundreds of micromolar) are disproportionally high with regard to physiological oxygen concentration (low micromolar). In this study using polarographic measurement of oxygen concentration in cellular suspensions we show that H₂O₂ addition results in O₂ release as expected from catalase reaction. This reaction is fast enough to, within seconds, decrease drastically H₂O₂ concentration and to annihilate it within a few minutes. Firstly, this is likely to explain why recording of oxidative damage requires the high concentrations found in the literature. Secondly, it illustrates the potency of intracellular antioxidant (H₂O₂) defense. Thirdly, it complicates the interpretation of experiments as subsequent observations might result from high/transient H2O2 exposure and/or from the diverse possible consequences of the O₂ release. as subsequent observations might result from high/transient H2O2 exposure and/or from the diverse possible consequences of the O₂ release.)
• Ratajczak 2019 Anal Bioanal Chem  + (Adenosine triphosphate (ATP) is the main e … Adenosine triphosphate (ATP) is the main energy source in cells and an important biomolecule participating in cellular reactions in living organisms. Since the ATP level changes dynamically reflecting the development of a debilitating disease or carcinogenesis, we have focused in this work on monitoring of the oligomycin (OMC)-modulated ATP synthase inhibition using a fluorescent-switching DNA aptamer designed for the detection of ATP (Apt(ATP)), as the model for studies of dynamic ATP level variation. The behavior of the ATP aptamer has been characterized using fluorescence spectroscopy. The Intramolecular fluorescence resonance energy transfer (iFRET) operates in the proposed aptamer from the FAM dye moiety to guanines of the aptamer G-quadruplex when the target ATP is present and binds to the aptamer changing its conformation. The iFRET process enables the detection of ATP down to the limit of detection, LOD = 17 μM, without resorting to any extra chemi-amplification schemes. The selectivity coefficients for relevant interferent triphosphates (UTP, GTP, and CTP) are low for the same concentration as that of ATP. We have demonstrated an efficient transfection of intact cells and OMC-treated SW480 colon cancer cells with Apt(ATP), using microscopic imaging, iFRET measurements, and cell viability testing with MTT method. The applicability of the switching DNA aptamer for the analysis of real samples, obtained by lysis of SW480 cells, was also tested. The proposed Apt(ATP) may be considered as a viable candidate for utilization in measurements of dynamic ATP level modulation in cells in different stages of cancer development and testing of new drugs in pharmacological studies.g of new drugs in pharmacological studies.)
• Baldini 2021 Life Sci  + (Adipocyte hypertrophy is the main cause of … Adipocyte hypertrophy is the main cause of obesity. A deeper understanding of the molecular mechanisms regulating adipocyte dysfunction may help to plan strategies to treat/prevent obesity and its metabolic complications. Here, we investigated ''in vitro'' the molecular alterations associated with early adipocyte hypertrophy, focusing on mitochondrial dysfunction.</br></br>As model of adipocyte hypertrophy, we employed 3T3-L1 preadipocytes firstly differentiated into mature adipocytes, then cultured with long-chain fatty acids. As a function of differentiation and hypertrophy, we assessed triglyceride content, lipid droplet size, radical homeostasis by spectrophotometry and microscopy, as well as the expression of PPARγ, adiponectin and metallothioneins. Mitochondrial status was investigated by electron microscopy, Oxygraph-2k (O2K) high-resolution respirometry, fluorimetry and western blot.</br></br>Compared to mature adipocytes, hypertrophic adipocytes showed increased triglyceride accumulation and lipid peroxidation, larger or unique lipid droplet, up-regulated expression of PPARγ, adiponectin and metallothioneins. At mitochondrial level, early-hypertrophic adipocytes exhibited: (i) impaired mitochondrial oxygen consumption with parallel reduction in the mitochondrial complexes; (ii) no changes in citrate synthase and HSP60 expression, and in the inner mitochondrial membrane polarization; (iii) no stimulation of mitochondrial fatty acid oxidation. Our findings indicate that the content, integrity, and catabolic activity of mitochondria were rather unchanged in early hypertrophic adipocytes, while oxygen consumption and oxidant production were altered.</br></br>In the model of early adipocyte hypertrophy exacerbated oxidative stress and impaired mitochondrial respiration were observed, likely depending on reduction in the mitochondrial complexes, without changes in mitochondrial mass and integrity.anges in mitochondrial mass and integrity.)
• Bikman 2022 Eur J Clin Nutr  + (Adipocyte mitochondrial respiration may in … Adipocyte mitochondrial respiration may influence metabolic fuel partitioning into oxidation versus storage, with implications for whole-body energy expenditure. Although insulin has been shown to influence mitochondrial respiration, the effects of dietary macronutrient composition have not been well characterized. The aim of this exploratory study was to test the hypothesis that a high-carbohydrate diet lowers the oxygen flux of adipocyte mitochondria ''ex vivo''. Among participants in a randomized-controlled weight-loss maintenance feeding trial, those consuming a high-carbohydrate diet (60% carbohydrate as a proportion of total energy, n = 10) had lower rates of maximal adipose tissue mitochondrial respiration than those consuming a moderate-carbohydrate diet (40%, n = 8, p = 0.039) or a low-carbohydrate diet (20%, n = 9, p = 0.005) after 10 to 15 weeks. This preliminary finding may provide a mechanism for postulated calorie-independent effects of dietary composition on energy expenditure and fat deposition, potentially through the actions of insulin on fuel partitioning.e actions of insulin on fuel partitioning.)
• Llobet 2015 Dis Model Mech  + (Adipogenesis is accompanied by differentia … Adipogenesis is accompanied by differentiation of adipose tissue-derived stem cells to adipocytes. As a part of this differentiation, biogenesis of the oxidative phosphorylation system occurs. Many chemical compounds used in medicine, agriculture, or other human activities, affect the oxidative phosphorylation function. Therefore, these xenobiotics could alter adipogenesis. We have analyzed the effects on adipocyte differentiation of some xenobiotics that act on the oxidative phosphorylation system. The tested concentrations have been previously reported in human blood. Our results show that pharmaceutical drugs that decrease mitochondrial DNA replication, such as nucleoside reverse transcriptase inhibitors, or inhibitors of mitochondrial protein synthesis, like ribosomal antibiotics, diminish adipocyte differentiation and leptin secretion. On the other hand, the environmental chemical pollutant tributyltin chloride, inhibiting the ATP synthase of the oxidative phosphorylation system, can promote adipocyte differentiation and leptin secretion, leading to obesity and metabolic syndrome as the obesogen hypothesis postulates.ome as the obesogen hypothesis postulates.)
• Shi 2023 Redox Biol  + (Adipose plasticity is critical for metabol … Adipose plasticity is critical for metabolic homeostasis. Adipocyte transdifferentiation plays an important role in adipose plasticity, but the molecular mechanism of transdifferentiation remains incompletely understood. Here we show that the transcription factor FoxO1 regulates adipose transdifferentiation by mediating Tgfβ1 signaling pathway. Tgfβ1 treatment induced whitening phenotype in beige adipocytes, reducing UCP1 and mitochondrial capacity and enlarging lipid droplets. Deletion of adipose FoxO1 (adO1KO) dampened Tgfβ1 signaling by downregulating Tgfbr2 and Smad3 and induced browning of adipose tissue in mice, increasing UCP1 and mitochondrial content and activating metabolic pathways. Silencing FoxO1 also abolished the whitening effect of Tgfβ1 on beige adipocytes. The adO1KO mice exhibited a significantly higher energy expenditure, lower fat mass, and smaller adipocytes than the control mice. The browning phenotype in adO1KO mice was associated with an increased iron content in adipose tissue, concurrent with upregulation of proteins that facilitate iron uptake (DMT1 and TfR1) and iron import into mitochondria (Mfrn1). Analysis of hepatic and serum iron along with hepatic iron-regulatory proteins (ferritin and ferroportin) in the adO1KO mice revealed an adipose tissue-liver crosstalk that meets the increased iron requirement for adipose browning. The FoxO1-Tgfβ1 signaling cascade also underlay adipose browning induced by β3-AR agonist CL316243. Our study provides the first evidence of a FoxO1-Tgfβ1 axis in the regulation of adipose browning-whitening transdifferentiation and iron influx, which sheds light on the compromised adipose plasticity in conditions of dysregulated FoxO1 and Tgfβ1 signaling.of dysregulated FoxO1 and Tgfβ1 signaling.)
• Lefranc 2019 Hypertension  + (Adipose tissue (AT) senescence and mitocho … Adipose tissue (AT) senescence and mitochondrial dysfunction are associated with obesity. Studies in obese patients and animals demonstrate that the MR (mineralocorticoid receptor) contributes to obesity-associated cardiovascular complications through its specific role in AT. However, underlying mechanisms remain unclear. This study aims to elucidate whether MR regulates mitochondrial function in obesity, resulting in AT premature aging and vascular dysfunction. Obese (db/db) and lean (db/+) mice were treated with an MR antagonist or a specific mitochondria-targeted antioxidant. Mitochondrial and vascular functions were determined by respirometry and myography, respectively. Molecular mechanisms were probed by Western immunoblotting and real-time polymerase chain reaction in visceral AT and arteries and focused on senescence markers and redox-sensitive pathways. db/db mice displayed AT senescence with activation of the p53-p21 pathway and decreased SIRT (sirtuin) levels, as well as mitochondrial dysfunction. Furthermore, the beneficial anticontractile effects of perivascular AT were lost in db/db via ROCK (Rho kinase) activation. MR blockade prevented these effects. Thus, MR activation in obesity induces mitochondrial dysfunction and AT senescence and dysfunction, which consequently increases vascular contractility. In conclusion, our study identifies novel mechanistic insights involving MR, adipose mitochondria, and vascular function that may be of importance to develop new therapeutic strategies to limit obesity-associated cardiovascular complications.y-associated cardiovascular complications.)
• Dela MiP2010  + (Adipose tissue exerts important endocrine … Adipose tissue exerts important endocrine and metabolic functions in health and disease. Yet the bioenergetics of this tissue is not characterized in humans and possible regional differences are not elucidated. Using high-resolution respirometry, mitochondrial respiration was quantified in human abdominal subcutaneous and intra-abdominal, visceral (omentum majus) adipose tissue from biopsies obtained in twenty obese patients undergoing bariatric surgery. [[mtDNA]] and gDNA were determined by PCR technique for estimation of mitochondrial density. Adipose tissue samples were permeabilized and respirometric measurements were performed in duplicate at 37 °C. Substrates [glutamate(G) + malate(M) + octanoyl carnitine(Oct) + succinate(S)] were added sequentially to provide electrons to Complexes CI + CII. ADP (D) for [[State 3]] respiration was added after GM. Non-coupled respiration was measured after addition of FCCP. Visceral fat contained more mitochondria per mg tissue than subcutaneous fat, but the cells were smaller. Robust, stable oxygen fluxes were found in both tissues, and coupled State 3 (GMOctSD) and non-coupled respiration were significantly (''P''<0.05) higher in visceral (0.95±0.05 and 1.15±0.06 pmol O2∙s^-1∙mg^-1, respectively) compared with subcutaneous (0.76±0.04 and 0.98±0.05 pmol O2∙s^-1∙mg^-1, respectively) adipose tissue. Expressed per mtDNA, visceral adipose tissue had significantly (''P''<0.05) lower mitochondrial respiration. Substrate control ratios were higher and uncoupling control ratio lower (''P''<0.05) in visceral compared with subcutaneous adipose tissue. </br></br>Visceral fat is bioenergetically more active and more sensitive to mitochondrial substrate supply than subcutaneous fat. [[OXPHOS]] has a higher relative activity in visceral compared with subcutaneous adipose tissue.s a higher relative activity in visceral compared with subcutaneous adipose tissue.)
• Kraunsoee 2010 J Physiol  + (Adipose tissue exerts important endocrine … Adipose tissue exerts important endocrine and metabolic functions in health and disease. Yet the bioenergetics of this tissue is not characterized in humans and possible regional differences are not elucidated. Using high-resolution respirometry, mitochondrial respiration was quantified in human abdominal subcutaneous and intra-abdominal visceral (omentum majus) adipose tissue from biopsies obtained in 20 obese patients undergoing bariatric surgery. Mitochondrial DNA (mtDNA) and genomic DNA (gDNA) were determined by the PCR technique for estimation of mitochondrial density. Adipose tissue samples were permeabilized and respirometric measurements were performed in duplicate at 37 °C. Substrates (glutamate (G) + malate (M) + octanoyl carnitine (Oct) + succinate (S)) were added sequentially to provide electrons to Complex I+II. ADP (_D) for State 3 respiration was added after GM. Non-coupled respiration was measured after addition of FCCP. Visceral fat contained more mitochondria per milligram of tissue than subcutaneous fat, but the cells were smaller. Robust, stable oxygen fluxes were found in both tissues, and coupled State 3 (GMOctS(D)) and non-coupled respiration were significantly (''P'' < 0.05) higher in visceral (0.95 +/- 0.05 and 1.15 +/- 0.06 pmol O(2) s^-1 mg^-1, respectively) compared with subcutaneous (0.76 +/- 0.04 and 0.98 +/- 0.05 pmol O(2) s^-1 mg^-1, respectively) adipose tissue. Expressed per mtDNA, visceral adipose tissue had significantly (''P'' < 0.05) lower mitochondrial respiration. Substrate control ratios were higher and uncoupling control ratio lower (''P'' < 0.05) in visceral compared with subcutaneous adipose tissue. We conclude that visceral fat is bioenergetically more active and more sensitive to mitochondrial substrate supply than subcutaneous fat. Oxidative phosphorylation has a higher relative activity in visceral compared with subcutaneous adipose tissue.Oxidative phosphorylation has a higher relative activity in visceral compared with subcutaneous adipose tissue.)
• Sahl 2021 Adipocyte  + (Adipose tissue mitochondrial function is g … Adipose tissue mitochondrial function is gaining increasing interest since it is good marker of overall health. Methodological challenges and variability in assessing mitochondrial respiration in fresh adipose tissue with high resolution respirometry are unknown and should be explored. Mitochondrial respiratory capacity (MRC) in human adipose tissue decline in a gradual manner when analyses are postponed 3h and 24h, with a statistically significant decline 24h after obtaining the biopsy. This decline in MRC is associated with a reduced integrity of the outer mitochondrial membrane at both time points. This study suggest that the optimal amount of tissue to be used is 20mg and that different technicians handling the biopsy do not affect MRC.ans handling the biopsy do not affect MRC.)
• Pino 2023 Abstract IOC162  + (Adipose tissue, which is the crucial energ … Adipose tissue, which is the crucial energy reservoir and endocrine organ for the maintenance of systemic glucose, lipid, and energy homeostasis, undergoes significant changes during aging. Ageing also impacts the circadian clock (CC) machinery of peripheral organs including white adipose tissue. Together, these alterations cause age-related disease in the elderly population. The aim of this study is to investigate the transcriptional expression of circadian clock genes, cell proliferation rates and mitochondrial capacity of adipose-derived stem cells (ASCs) isolated from abdominal subcutaneous white adipose tissue (scWAT) from old and young individuals.</br></br>10 old (5 females) and 10 young individuals (5 females) participated in this study. To measure CC related genes, proliferating ASCs were synchronized with 30% fetal bovine serum (FBS) for two hours, then media was replaced with 2% FBS and RNA was collected every six hours for a duration of 48 hrs and targeted gene expression was measured by qRT-PCR. To measure cells proliferation, ASCs were plated in 96 well plate and cell proliferation was measured with CellTiter-Glow luminescent cell viability kit (Promega, USA) for a period of 72 hrs. Mitochondrial capacity, oxygen consumption rates, were measured in proliferating ASCs via high-resolution respirometry using the Oxygraph-2K (Oroboros instruments, Innsbruck, Austria).</br></br>An increase in mRNA levels of CLOCK and PER2 and a loss of rhythmicity for CLOCK and CRY1 were observed in ASCs from older individuals compared to the young. mRNA levels and rhythmicity of BMAL, PER1, DBP, NR1D1 and NR1D2 were not altered by age. We are currently determining cell proliferation and mitochondrial capacity in ASCs. Overall, age does not seem to affect CC rhythmicity in ASCs isolated from scWAT from old and young individuals.from scWAT from old and young individuals.)
• Irion 2020 Stem Cells Int  + (Adipose-derived mesenchymal stromal cell ( … Adipose-derived mesenchymal stromal cell (AD-MSC) administration improves cardiac function after acute myocardial infarction (AMI). Although the mechanisms underlying this effect remain to be elucidated, the reversal of the mitochondrial dysfunction may be associated with AMI recovery. Here, we analyzed the alterations in the respiratory capacity of cardiomyocytes in the infarcted zone (IZ) and the border zone (BZ) and evaluated if mitochondrial function improved in cardiomyocytes after AD-MSC transplantation. Female rats were subjected to AMI by permanent left anterior descending coronary (LAD) ligation and were then treated with AD-MSCs or PBS in the border zone (BZ). Cardiac fibers were analyzed 24 hours (necrotic phase) and 8 days (fibrotic phase) after AMI for mitochondrial respiration, citrate synthase (CS) activity, F₀F₁-ATPase activity, and transmission electron microscopy (TEM). High-resolution respirometry of permeabilized cardiac fibers showed that AMI reduced numerous mitochondrial respiration parameters in cardiac tissue, including phosphorylating and nonphosphorylating conditions, respiration coupled to ATP synthesis, and maximal respiratory capacity. CS decreased in IZ and BZ at the necrotic phase, whereas it recovered in BZ and continued to drop in IZ over time when compared to Sham. Exogenous cytochrome c doubled respiration at the necrotic phase in IZ. F₀F₁-ATPase activity decreased in the BZ and, to more extent, in IZ in both phases. Transmission electron microscopy showed disorganized mitochondrial cristae structure, which was more accentuated in IZ but also important in BZ. All these alterations in mitochondrial respiration were still present in the group treated with AD-MSC. In conclusion, AMI led to mitochondrial dysfunction with oxidative phosphorylation disorders, and AD-MSC improved CS temporarily but was not able to avoid alterations in mitochondria function over time.d CS temporarily but was not able to avoid alterations in mitochondria function over time.)
• Santos-Silva 2023 Transl Psychiatry  + (Adolescent individuals exhibit great varia … Adolescent individuals exhibit great variability in cortical dynamics and behavioral outcomes. The developing adolescent brain is highly sensitive to social experiences and environmental insults, influencing how personality traits emerge. A distinct pattern of mitochondrial gene expression in the prefrontal cortex (PFC) during adolescence underscores the essential role of mitochondria in brain maturation and the development of mental illnesses. Mitochondrial features in certain brain regions account for behavioral differences in adulthood. However, it remains unclear whether distinct adolescent behavioral phenotypes and the behavioral consequences of early adolescent stress exposure in rats are accompanied by changes in PFC mitochondria-related genes and mitochondria respiratory chain capacity. We performed a behavioral characterization during late adolescence (postnatal day, PND 47-50), including naïve animals and a group exposed to stress from PND 31-40 (10 days of footshock and 3 restraint sessions) by z-normalized data from three behavioral domains: anxiety (light-dark box tests), sociability (social interaction test) and cognition (novel-object recognition test). Employing principal component analysis, we identified three clusters: naïve with higher-behavioral z-score (HBZ), naïve with lower-behavioral z-score (LBZ), and stressed animals. Genome-wide transcriptional profiling unveiled differences in the expression of mitochondria-related genes in both naïve LBZ and stressed animals compared to naïve HBZ. Genes encoding subunits of oxidative phosphorylation complexes were significantly down-regulated in both naïve LBZ and stressed animals and positively correlated with behavioral z-score of phenotypes. Our network topology analysis of mitochondria-associated genes found Ndufa10 and Cox6a1 genes as central identifiers for naïve LBZ and stressed animals, respectively. Through high-resolution respirometry analysis, we found that both naïve LBZ and stressed animals exhibited a reduced prefrontal phosphorylation capacity and redox dysregulation. Our findings identify an association between mitochondrial features and distinct adolescent behavioral phenotypes while also underscoring the detrimental functional consequences of adolescent stress on the PFC.sequences of adolescent stress on the PFC.)
• Mahdaviani 2014 Abstract MiP2014  + (Adrenergic stimulation of brown adipocytes … Adrenergic stimulation of brown adipocytes (BA) induces mitochondrial uncoupling, thereby increasing energy expenditure by shifting nutrient oxidation towards thermogenesis [1]. The brown adipocyte is a unique system to study the relationship between mitochondrial architecture and bioenergetic function. Here we describe that mitochondrial dynamics is a physiological regulator of adrenergically‐induced changes in energy expenditure. </br>Brown pre-adipocyes were harvested from 4-week-old wild-type male C57BL6/J mice and differentiated in culture. Oxygen consumption was measured using Seahorse XF24. Mitochondrial membrane potential was measured using TMRE and Zeiss LSM 710 confocal microscope. Measurements were taken before and after activation with NE (1 uM) and FFA (palmitate or oleate, 0.4 mM).</br></br>The sympathetic neurotransmitter norepinephrine (NE) induced complete and rapid mitochondrial fragmentation in BA, characterized by Drp1 phosphorylation and Opa1 cleavage. Mechanistically, NE‐mediated Drp1 phosphorylation was dependent on protein kinase‐A (PKA) activity [2], whereas Opa1 cleavage required mitochondrial depolarization, mediated by FFAs released as a result of lipolysis. This change in mitochondrial architecture was observed both in primary cultures and brown adipose tissue from cold‐exposed mice. Mitochondrial uncoupling, induced by NE in brown adipocytes, was reduced by inhibition of mitochondrial fission through transient Drp1 DN overexpression. Furthermore, forced mitochondrial fragmentation in BA through Mfn2 knock down increased the capacity of exogenous FFAs to increase energy expenditure.</br></br>These results suggest that, in addition to its ability to stimulate lipolysis, NE induces energy expenditure in BA by promoting mitochondrial fragmentation. Taken together these data reveal that adrenergically‐induced changes of mitochondrial dynamics are required for BA thermogenic activation and for the control of energy expenditure.and for the control of energy expenditure.)
• Anmann 2014 Biochim Biophys Acta  + (Adult cardiomyocytes have highly organized … Adult cardiomyocytes have highly organized intracellular structure and energy metabolism whose formation during postnatal development is still largely unclear. Our previous results together with the data from the literature suggest that cytoskeletal proteins, particularly βII-tubulin, are involved in the formation of complexes between mitochondria and energy consumption sites. The aim of this study was to examine the arrangement of intracellular architecture parallel to the alterations in regulation of mitochondrial respiration in rat cardiomyocytes during postnatal development, from 1day to 6months. Respirometric measurements were performed to study the developmental alterations of mitochondrial function. Changes in the mitochondrial arrangement and cytoarchitecture of βII- and αIV-tubulin were examined by confocal microscopy. Our results show that functional maturation of oxidative phosphorylation in mitochondria is completed much earlier than efficient feedback regulation is established between mitochondria and ATPases via creatine kinase system. These changes are accompanied by significant remodeling of regular intermyofibrillar mitochondrial arrays aligned along the bundles of βII-tubulin. Additionally, we demonstrate that formation of regular arrangement of mitochondria is not sufficient per se to provide adult-like efficiency in metabolic feed-back regulation, but organized tubulin networks and reduction in mitochondrial outer membrane permeability for ADP are necessary as well. In conclusion, cardiomyocytes in rat heart become mature on the level of intracellular architecture and energy metabolism at the age of 3months.d energy metabolism at the age of 3months.)
• Soares 2015 PLoS One  + (Adult females of ''Aedes aegypti'' are fac … Adult females of ''Aedes aegypti'' are facultative blood sucking insects and vectors of Dengue and yellow fever viruses. Insect dispersal plays a central role in disease transmission and the extremely high energy demand posed by flight is accomplished by a very efficient oxidative phosphorylation process, which take place within flight muscle mitochondria. These organelles play a central role in energy metabolism, interconnecting nutrient oxidation to ATP synthesis, but also represent an important site of cellular superoxide production. Given the importance of mitochondria to cell physiology, and the potential contributions of this organelle for ''A. aegypti'' biology and vectorial capacity, here, we conducted a systematic assessment of mitochondrial physiology in flight muscle of young adult ''A. aegypti'' fed exclusively with sugar. This was carried out by determining the activities of mitochondrial enzymes, the substrate preferences to sustain respiration, the mitochondrial bioenergetic efficiency and capacity, in both mitochondria-enriched preparations and mechanically permeabilized flight muscle in both sexes. We also determined the substrates preferences to promote mitochondrial superoxide generation and the main sites where it is produced within this organelle. We observed that respiration in ''A. aegypti'' mitochondria was essentially driven by complex I and glycerol 3 phosphate dehydrogenase substrates, which promoted distinct mitochondrial bioenergetic capacities, but with preserved efficiencies. Respiration mediated by proline oxidation in female mitochondria was strikingly higher than in males. Mitochondrial superoxide production was essentially mediated through proline and glycerol 3 phosphate oxidation, which took place at sites other than complex I. Finally, differences in mitochondrial superoxide production among sexes were only observed in male oxidizing glycerol 3 phosphate, exhibiting higher rates than in female. Together, these data represent a significant step towards the understanding of fundamental mitochondrial processes in ''A. aegypti'', with potential implications for its physiology and vectorial capacity.for its physiology and vectorial capacity.)
• Bennett 2021 Biomedicines  + (Adult human brains consume a disproportion … Adult human brains consume a disproportionate amount of energy substrates (2-3 % of body weight; 20-25 % of total glucose and oxygen). Adenosine triphosphate (ATP) is a universal energy currency in brains and is produced by oxidative phosphorylation (OXPHOS) using ATP synthase, a nano-rotor powered by the proton gradient generated from proton-coupled electron transfer (PCET) in the multi-complex electron transport chain (ETC). ETC catalysis rates are reduced in brains from humans with neurodegenerative diseases (NDDs). Declines of ETC function in NDDs may result from combinations of nitrative stress (NS)-oxidative stress (OS) damage; mitochondrial and/or nuclear genomic mutations of ETC/OXPHOS genes; epigenetic modifications of ETC/OXPHOS genes; or defects in importation or assembly of ETC/OXPHOS proteins or complexes, respectively; or alterations in mitochondrial dynamics (fusion, fission, mitophagy). Substantial free energy is gained by direct O2-mediated oxidation of NADH. Traditional ETC mechanisms require separation between O2 and electrons flowing from NADH/FADH2 through the ETC. Quantum tunneling of electrons and much larger protons may facilitate this separation. Neuronal death may be viewed as a local increase in entropy requiring constant energy input to avoid. The ATP requirement of the brain may partially be used for avoidance of local entropy increase. Mitochondrial therapeutics seeks to correct deficiencies in ETC and OXPHOS.to correct deficiencies in ETC and OXPHOS.)
• Teulier 2018 J Fish Biol  + (Adult zebrafish ''Danio rerio'' were expos … Adult zebrafish ''Danio rerio'' were exposed to an electric shock of 3 V and 1A for 5 s delivered by field backpack electrofishing gear, to induce a taxis followed by a narcosis. The effect of such electric shock was investigated on both the individual performances (swimming capacities and costs of transport) and at cellular and mitochondrial levels (oxygen consumption and oxidative balance). The observed survival rate was very high (96·8%) independent of swimming speed (up to 10 body length s^-1). The results showed no effect of the treatment on the metabolism and cost of transport of the fish. Nor did the electroshock trigger any changes on muscular oxidative balance and bioenergetics even if red muscle fibres were more oxidative than white muscle. Phosphorylating respiration rates rose between (mean 1 s.e.) 11·16 ± 1·36 pmol O₂ s^-1 mg^-1 and 15·63 ± 1·60 pmol O₂ s^-1 mg^-1 for red muscle fibres whereas phosphorylating respiration rates only reached 8·73 ± 1·27 pmol O₂ s^-1 mg^-1 in white muscle. Such an absence of detectable physiological consequences after electro-induced narcosis both at organismal and cellular scales indicate that this capture method has no apparent negative post-shock performance under the conditions of this study.cosis both at organismal and cellular scales indicate that this capture method has no apparent negative post-shock performance under the conditions of this study.)
• Benes 2011 Clin Sci (Lond)  + (Advanced HF (heart failure) is associated … Advanced HF (heart failure) is associated with altered substrate metabolism. Whether modification of substrate use improves the course of HF remains unknown. The antihyperglycaemic drug MET (metformin) affects substrate metabolism, and its use might be associated with improved outcome in diabetic HF. The aim of the present study was to examine whether MET would improve cardiac function and survival also in non-diabetic HF. Volume-overload HF was induced in male Wistar rats by creating ACF (aortocaval fistula). Animals were randomized to placebo/MET (300 mg·kg(-1) of body weight·day(-1), 0.5% in food) groups and underwent assessment of metabolism, cardiovascular and mitochondrial functions (n=6-12/group) in advanced HF stage (week 21). A separate cohort served for survival analysis (n=10-90/group). The ACF group had marked cardiac hypertrophy, increased LVEDP (left ventricular end-diastolic pressure) and lung weight confirming decompensated HF, increased circulating NEFAs (non-esterified 'free' fatty acids), intra-abdominal fat depletion, lower glycogen synthesis in the skeletal muscle (diaphragm), lower myocardial triacylglycerol (triglyceride) content and attenuated myocardial (14)C-glucose and (14)C-palmitate oxidation, but preserved mitochondrial respiratory function, glucose tolerance and insulin sensitivity. MET therapy normalized serum NEFAs, decreased myocardial glucose oxidation, increased myocardial palmitate oxidation, but it had no effect on myocardial gene expression, AMPK (AMP-activated protein kinase) signalling, ATP level, mitochondrial respiration, cardiac morphology, function and long-term survival, despite reaching therapeutic serum levels (2.2±0.7 μg/ml). In conclusion, MET-induced enhancement of myocardial fatty acid oxidation had a neutral effect on cardiac function and survival. Recently reported cardioprotective effects of MET may not be universal to all forms of HF and may require AMPK activation or ATP depletion. No increase in mortality on MET supports its safe use in diabetic HF. MET supports its safe use in diabetic HF.)
• National Academies of Sciences, Engineering, and Medicine 2018 Science data infrastructure  + (Advances in science and technology have le … Advances in science and technology have led to the creation of large amounts of data—data that could be harnessed to improve productivity, cure disease, and address many other critical issues. Consensus in the scientific community is growing that the transition to truly data-driven and open science is best achieved by the establishment of a globally interoperable research infrastructure.</br>A number of projects are looking to establish this infrastructure and exploit data to its fullest potential. Several projects in the United States, Europe, and China have made significant strides toward this effort. The goal of these projects is to make research data findable, accessible, interoperable, and reusable, or FAIR (see Box 1). The expected impact and benefits of FAIR data are substantial. To realize these benefits, there is a need to examine critical success factors for implementation, including training of a new generation of data experts to provide the necessary capacity.</br></br>On November 1, 2017, the Board on Research Data and Information (BRDI) of the National Academies of</br>Sciences, Engineering, and Medicine organized a symposium to explore these issues. Invited experts from China, Europe, and the United States were asked to:</br>* Review proposed science data infrastructure projects around the globe;</br>* Highlight, compare, and contrast the plans and capabilities of these projects; and</br>* Discuss the critical success factors for implementation and the role of international cooperation for scientific data management.ooperation for scientific data management.)
• Cedrone 2019 Thesis  + (Adverse ''in utero'' and postnatal conditi … Adverse ''in utero'' and postnatal conditions can increase susceptibility to metabolic syndrome (MS). Altered muscle respiration contributes to MS, but the effects of restricted oxygen and nutrients ''in utero'' on skeletal muscle mitochondria remain unknown. In this study guinea pig sows underwent uterine artery ablations mid-gestation, producing fetuses with low birth weight (LBW). Soleus muscle was collected near term or at four months of age, from LBW and control fetuses and offspring, where the offspring were fed either a Western Diet (WD) or a control diet (CD). Soleus muscles from LBW fetuses exhibit lower maximal respiration rates than normal birth weight (NBW) sham-surgery controls. Additionally, LBW/CD, NBW/WD and LBW/WD adult guinea pigs displayed reduced respiration compared with NBW/CD. Cultured C2C12 cells were utilized to better understand independent effects of hypoxia and fatty acid saturation upon cellular respiration. Both chronic (5 days) hypoxia and palmitate (16:0) reduced respiration compared with normoxia.educed respiration compared with normoxia.)
• Santana-Roman 2021 Insects  + (Aedes aegypti and Aedes albopictus mosquit … Aedes aegypti and Aedes albopictus mosquitoes are responsible for dengue virus (DENV) transmission in tropical and subtropical areas worldwide, where an estimated 3 billion people live at risk of DENV exposure. DENV-infected individuals show symptoms ranging from sub-clinical or mild to hemorrhagic fever. Infected mosquitoes do not show detectable signs of disease, even though the virus maintains a lifelong persistent infection. The interactions between viruses and host mitochondria are crucial for virus replication and pathogenicity. DENV infection in vertebrate cells modulates mitochondrial function and dynamics to facilitate viral proliferation. Here, we describe that DENV also regulates mitochondrial function and morphology in infected C6/36 mosquito cells (derived from Aedes albopictus). Our results showed that DENV infection increased ROS (reactive oxygen species) production, modulated mitochondrial transmembrane potential and induced changes in mitochondrial respiration. Furthermore, we offer the first evidence that DENV causes translocation of mitofusins to mitochondria in the C6/36 mosquito cell line. Another protein Drp-1 (Dynamin-related protein 1) did not localize to mitochondria in DENV-infected cells. This observation therefore ruled out the possibility that the abovementioned alterations in mitochondrial function are associated with mitochondrial fission. In summary, this report provides some key insights into the virus-mitochondria crosstalk in DENV infected mosquito cells.crosstalk in DENV infected mosquito cells.)
• Espino 2016 Abstract Mito Xmas Meeting Innsbruck  + (Aequorin is a 22-kDa photoprotein produced … Aequorin is a 22-kDa photoprotein produced by the jellyfish ''Aequorea victoria'' that has been long utilised for the study of Ca²⁺ signaling [1]. It has been also engineered to induce its specific targeting to various cell regions so as to monitor [Ca²⁺] in different subcellular comparments, e.g., mitochondrial matrix [2]. Nevertheless, its potential applicability is somewhat limited owing to consumption or saturation of aequorin throughout the experiment as well as stability of aequorin at physiological temperature. Herein, in an attempt to overcome the aforementioned disadvantages, we have developed a mitochondria-targeted triple-mutated form (Asp119Ala, Gln168Arg and Leu170Ile) of the photoprotein aequorin that enables measurement of [Ca²⁺] in the millimolar range. In fact, it is shown that addition of extramitochondrial Ca²⁺ to permeabilized HeLa cells triggers an increase in mitochondrial [Ca²⁺] up to approximately 2 mM. In intact cells, the novel probe allows recording agonist-stimulated mitochondrial [Ca²⁺] rises without problems derived from aequorin saturation and/or consumption. Notably, in addition to the increased dynamic range, the Gln168Arg and Leu170Ile mutations endowed this new aequorin-based probe with an increased lifetime at 37°C. This also allowed the generation of a cell line stably expressing the probe at very high levels.lifetime at 37°C. This also allowed the generation of a cell line stably expressing the probe at very high levels.)
• Eynon 2011 Physiol Genomics  + (Aerobic ATP generation by the mitochondria … Aerobic ATP generation by the mitochondrial respiratory oxidative phosphorylation system (OXPHOS) is a vital metabolic process for endurance exercise. Notably, mitochondrial DNA (mtDNA) codifies 13 of the 83 polypeptides implied in the respiratory chain. As such, there is a strong rationale for identifying an association between mtDNA variants and "aerobic" (endurance) exercise phenotypes. The aim of this review is to summarize current knowledge on the association between mtDNA, nuclear genes involved in mitochondriogenesis, and elite endurance athletic status. Several studies in nonathletic people have demonstrated an association between certain mtDNA lineages and aerobic performance, characterized by maximal oxygen uptake (VO2max). Whether mtDNA haplogroups are also associated with the status of being an elite endurance athlete is more controversial, with differences between studies arising from the different ethnic backgrounds of the athletic cohorts (Caucasian of mixed geographic origin, Asiatic, or East African).graphic origin, Asiatic, or East African).)

• Hunter 2019 J Appl Physiol (1985)  + (Aerobic capacity is negatively related to … Aerobic capacity is negatively related to locomotion economy. The purpose of the paper is to determine what effects aerobic exercise training has on the relationship between net cycling oxygen uptake (inverse of economy) and aerobic capacity (VO_2peak) as well as what role mitochondrial coupled and uncoupled respiration may play in whole body aerobic capacity and cycling economy.</br></br>Cycling net oxygen uptake and VO_2peak were evaluated on 52 subjects prior to exercise training (baseline) and 31 subjects after 8-16 weeks of aerobic training. Muscle tissue was collected from 25 subjects at baseline and 15 post training. Mitochondrial respiration assays were performed using High Resolution Respirometry.</br></br>Pre (r=0.34, p<0.05) and post exercise training (r=0.62, p<0.01) VO_2peak and cycling net oxygen uptake were related. In addition, uncoupled and coupled fat respiration were related both baseline (r=0.89, p<0.01) and post training (r=0.89, p<01). Post training coupled (r=0.74, p<0.01) and uncoupled carbohydrate respiration (r=0.52, p<05) were related to cycle net oxygen uptake. In addition, correlations between changes in VO_2peak and changes in cycle net oxygen uptake persist after training, even after adjusting for changes in RQ (an index of fat oxidation).</br></br>These results suggest that the negative relationship between locomotion economy and aerobic capacity is increased following exercise training. In addition, it is proposed that at least one of the primary factors influencing this relationship has its foundation within the mitochondria. Strong relationships between coupled and uncoupled respiration appear to be contributing factors for this relationship.tionships between coupled and uncoupled respiration appear to be contributing factors for this relationship.)
• Hunter 2019 J Appl Physiol  + (Aerobic capacity is negatively related to … Aerobic capacity is negatively related to locomotion economy. The purpose of this paper is to determine what effect aerobic exercise training has on the relationship between net cycling oxygen uptake (inverse of economy) and aerobic capacity [peak oxygen uptake (V̇o2peak)], as well as what role mitochondrial coupled and uncoupled respiration may play in whole body aerobic capacity and cycling economy. Cycling net oxygen uptake and ''V̇''o2peak were evaluated on 31 premenopausal women before exercise training (baseline) and after 8-16 wk of aerobic training. Muscle tissue was collected from 15 subjects at baseline and post-training. Mitochondrial respiration assays were performed using high-resolution respirometry. Pre- (''r'' = 0.46, ''P'' < 0.01) and postexercise training (''r'' = 0.62, ''P'' < 0.01) ''V̇''o2peak and cycling net oxygen uptake were related. In addition, uncoupled and coupled fat respiration were related both at baseline (''r'' = 0.62, ''P'' < 0.01) and post-training (''r'' = 0.89, ''P'' < 01). Post-training coupled (''r'' = 0.74, ''P'' < 0.01) and uncoupled carbohydrate respiration (''r'' = 0.52, ''P'' < 05) were related to cycle net oxygen uptake. In addition, correlations between ''V̇''o2peak and cycle net oxygen uptake persist both at baseline and after training, even after adjusting for submaximal cycle respiratory quotient (an index of fat oxidation). These results suggest that the negative relationship between locomotion economy and aerobic capacity is increased following exercise training. In addition, it is proposed that at least one of the primary factors influencing this relationship has its foundation within the mitochondria. Strong relationships between coupled and uncoupled respiration appear to be contributing factors for this relationship.</br></br>NEW & NOTEWORTHY: The negative relationship between cycle economy and aerobic capacity is increased following exercise training. The strong relationship between coupled and uncoupled respiration, especially after training, appears to be contributing to this negative relationship between aerobic capacity and cycling economy, suggesting that mitochondrial economy is not increased following aerobic exercise training. These results are suggestive that training programs designed to improve locomotion economy should focus on changing biomechanics.mprove locomotion economy should focus on changing biomechanics.)
• Dawson 2022 FASEB J  + (Aerobic energy demands have led to the evo … Aerobic energy demands have led to the evolution of complex mitochondrial reticula in highly oxidative muscles, but the extent to which metabolic challenges can be met with adaptive changes in physiology of specific mitochondrial fractions remains unresolved. We examined mitochondrial mechanisms supporting adaptive increases in aerobic performance in deer mice (''Peromyscus maniculatus'') adapted to the hypoxic environment at high altitude. High-altitude and low-altitude mice were born and raised in captivity, and exposed as adults to normoxia or hypobaric hypoxia (12 kPa O₂ for 6-8 weeks). Subsarcolemmal and intermyofibrillar mitochondria were isolated from the gastrocnemius, and a comprehensive substrate titration protocol was used to examine mitochondrial physiology and O₂ kinetics by high-resolution respirometry and fluorometry. High-altitude mice had greater yield, respiratory capacity for oxidative phosphorylation, and O₂ affinity (lower P50 ) of subsarcolemmal mitochondria compared to low-altitude mice across environments, but there were no species difference in these traits in intermyofibrillar mitochondria. High-altitude mice also had greater capacities of complex II relative to complexes I + II and higher succinate dehydrogenase activities in both mitochondrial fractions. Exposure to chronic hypoxia reduced reactive oxygen species (ROS) emission in high-altitude mice but not in low-altitude mice. Our findings suggest that functional changes in subsarcolemmal mitochondria contribute to improving aerobic performance in hypoxia in high-altitude deer mice. Therefore, physiological variation in specific mitochondrial fractions can help overcome the metabolic challenges of life at high altitude.fractions can help overcome the metabolic challenges of life at high altitude.)
• Gnaiger 2005 Abstract MiP2005  + (Aerobic exercise and several aspects of li … Aerobic exercise and several aspects of life style influence mitochondrial respiratory function in human muscle, in addition to effects of age, gender and genetic background. In the present study, a significant part of the variability in respiration of human mitochondria [1] was explained by analysis of readily accessible background information on 25 healthy human subjects (19 males and 6 females; 22 to 46 years). Based on a novel multi-substrate/inhibitor protocol, this approach advances the functional analysis in mitochondrial physiology and pathology.</br></br>A protocol for high-resolution respirometry (with two or three Oroboros Oxygraph-2k operated in parallel) was designed for quantification of mitochondrial respiratory capacities in permeabilized muscle fibers obtained from small needle biopsies (2 to 6 mg per run; 2 or 4 runs per subject). Cell membranes were selectively permeabilized [2], and lack of respiratory stimulation by cytochrome c indicated an intact outer mitochondrial membrane (Fig. 1). Measurements were performed at 30 °C in the range of 20 to 50 kPa oxygen pressure (210 to 530 µM), to avoid oxygen limitation [3]. In this range, autoxidation of ascorbate and TMPD was a linear function of oxygen, which was applied for correction of chemical background oxygen flux.</br></br>ADP-stimulated respiration with malate+octanoylcarnitine (state OM3) was 46 % compared to further addition of glutamate (state GM3). An additive effect was exerted by parallel complex I+II electron input (the GS3/GM3 ratio was 1.6), since respiration with succinate/rotenone (S3) was only 1.1 times the state GM3 (Fig. 1). In a variation of this protocol, FCCP was titrated upon state GS3, yielding a further 44 % increase (and a corresponding GSu/GM3 ratio of 2.4). State GS3, therefore, reflects the capacity of the phosphorylation system, in agreement with results on isolated mitochondria [4]. The coupled state GS3 represents the physiologically relevant upper limit of respiration, providing parallel complex I and II input in accordance with an operational TCA cycle. The physiological excess capactiy of COX, expressed as the COX/GM3 ratio was 2.7, whereas the COX/GS3 ratio was 1.4. Respiratory adenylate control ratios were identical with octanoylcarnitie (OM3/OM2) and succinate (S3/S4o).</br></br>State GS3 declined significantly as a function of body mass index (BMI; body weight/hight2) in the 19 males, which explained ~60 % of total variability. BMI was independent of age, as was the GS3 respiratory capacity. Fatty acid oxidation capacity (state OM3), however, declined significantly with age (males and females combined), thus extending a study on isolated mitochondria [1] to a surprisingly narrow range of ages. Consideration of BMI and age, therefore, improves the diagnostic resolution of functional mitochondrial respiratory analyses.tional mitochondrial respiratory analyses.)
• Suhane 2013 Bio Open  + (Aerobic glycolysis in transformed cells is … Aerobic glycolysis in transformed cells is an unique metabolic phenotype characterized by a hyperactivated glycolytic pathway even in the presence of oxygen. It is not clear if the onset of aerobic glycolysis is regulated by mitochondrial dysfunction and, if so, what the metabolic windows of opportunity available to control this metabolic switch (mitochondrial to glycolytic) landscape are in transformed cells. Here we report a genetically-defined model system based on the gene-silencing of a mitochondrial complex I subunit, NDUFS3, where we demonstrate the onset of metabolic switch in isogenic human embryonic kidney cells by differential expression of NDUFS3. By means of extensive metabolic characterization, we demonstrate that NDUFS3 gene silencing systematically introduces mitochondrial dysfunction thereby leading to the onset of aerobic glycolysis in a manner dependent on NDUFS3 protein levels. Furthermore, we show that the sustained imbalance in free radical dynamics is a necessary condition to sustain the observed metabolic switch in cell lines with the most severe NDUFS3 suppression. Together, our data reveal a novel role for mitochondrial complex I subunit NDUFS3 in regulating the degree of mitochondrial dysfunction in living cells, thereby setting a “metabolic threshold” for the observation of aerobic glycolysis phenotype within the confines of mitochondrial dysfunction.the confines of mitochondrial dysfunction.)
• Jia 2018 Cells  + (Aerobic glycolysis, also referred to as th … Aerobic glycolysis, also referred to as the Warburg effect, has been regarded as the dominant metabolic phenotype in cancer cells for a long time. More recently, it has been shown that mitochondria in most tumors are not defective in their ability to carry out oxidative phosphorylation (OXPHOS). Instead, in highly aggressive cancer cells, mitochondrial energy pathways are reprogrammed to meet the challenges of high energy demand, better utilization of available fuels and macromolecular synthesis for rapid cell division and migration. Mitochondrial energy reprogramming is also involved in the regulation of oncogenic pathways via mitochondria-to-nucleus retrograde signaling and post-translational modification of oncoproteins. In addition, neoplastic mitochondria can engage in crosstalk with the tumor microenvironment. For example, signals from cancer-associated fibroblasts can drive tumor mitochondria to utilize OXPHOS, a process known as the reverse Warburg effect. Emerging evidence shows that cancer cells can acquire a hybrid glycolysis/OXPHOS phenotype in which both glycolysis and OXPHOS can be utilized for energy production and biomass synthesis. The hybrid glycolysis/OXPHOS phenotype facilitates metabolic plasticity of cancer cells and may be specifically associated with metastasis and therapy-resistance. Moreover, cancer cells can switch their metabolism phenotypes in response to external stimuli for better survival. Taking into account the metabolic heterogeneity and plasticity of cancer cells, therapies targeting cancer metabolic dependency in principle can be made more effective.y in principle can be made more effective.)
• Saura 2022 Proc Natl Acad Sci U S A  + (Aerobic life is powered by membrane-bound … Aerobic life is powered by membrane-bound enzymes that catalyze the transfer of electrons to oxygen and protons across a biological membrane. Cytochrome c oxidase (CcO) functions as a terminal electron acceptor in mitochondrial and bacterial respiratory chains, driving cellular respiration and transducing the free energy from O2 reduction into proton pumping. Here we show that CcO creates orientated electric fields around a nonpolar cavity next to the active site, establishing a molecular switch that directs the protons along distinct pathways. By combining large-scale quantum chemical density functional theory (DFT) calculations with hybrid quantum mechanics/molecular mechanics (QM/MM) simulations and atomistic molecular dynamics (MD) explorations, we find that reduction of the electron donor, heme ''a'', leads to dissociation of an arginine (Arg438)-heme a3 D-propionate ion-pair. This ion-pair dissociation creates a strong electric field of up to 1 V Å-1 along a water-mediated proton array leading to a transient proton loading site (PLS) near the active site. Protonation of the PLS triggers the reduction of the active site, which in turn aligns the electric field vectors along a second, "chemical," proton pathway. We find a linear energy relationship of the proton transfer barrier with the electric field strength that explains the effectivity of the gating process. Our mechanism shows distinct similarities to principles also found in other energy-converting enzymes, suggesting that orientated electric fields generally control enzyme catalysis.fields generally control enzyme catalysis.)
• Thoral 2021 Biol Lett  + (Aerobic metabolism of aquatic ectotherms i … Aerobic metabolism of aquatic ectotherms is highly sensitive to fluctuating climates. Many mitochondrial traits exhibit phenotypic plasticity in response to acute variations in temperature and oxygen availability. These responses are critical for understanding the effects of environmental variations on aquatic ectotherms' performance. Using the European seabass, ''Dicentrarchus labrax'', we determined the effects of acute warming and deoxygenation ''in vitro'' on mitochondrial respiratory capacities and mitochondrial efficiency to produce ATP (ATP/O ratio). We show that acute warming reduced ATP/O ratio but deoxygenation marginally raised ATP/O ratio, leading to a compensatory effect of low oxygen availability on mitochondrial ATP/O ratio at high temperature. The acute effect of warming and deoxygenation on mitochondrial efficiency might be related to the leak of protons across the mitochondrial inner membrane, as the mitochondrial respiration required to counteract the proton leak increased with warming and decreased with deoxygenation. Our study underlines the importance of integrating the combined effects of temperature and oxygen availability on mitochondrial metabolism. Predictions on decline in performance of aquatic ectotherms owing to climate change may not be accurate, since these predictions typically look at respiratory capacity and ignore efficiency of ATP production.y and ignore efficiency of ATP production.)
• Wone 2013 Comp Biochem Physiol A Mol Integr Physiol  + (Aerobic metabolism of vertebrates is linke … Aerobic metabolism of vertebrates is linked to membrane fatty acid (FA) composition. Although the membrane pacemaker hypothesis posits that desaturation of FAs accounts for variation in resting or basal metabolic rate (BMR), little is known about the FA profiles that underpin variation in maximal metabolic rate (MMR). We examined membrane FA composition of liver and skeletal muscle in mice after seven generations of selection for increased MMR. In both liver and skeletal muscle, unsaturation index did not differ between control and high-MMR mice. We also examined membrane FA composition at the individual-level of variation. In liver, 18:0, 20:3 n-6, 20:4 n-6, and 22:6 n-3 FAs were significant predictors of MMR. In gastrocnemius muscle, 18:2 n-6, 20:4 n-6, and 22:6 n-3 FAs were significant predictors of MMR. In addition, muscle 16:1 n-7, 18:1 n-9, and 22:5 n-3 FAs were significant predictors of BMR, whereas no liver FAs were significant predictors of BMR. Our findings indicate that (i) individual variation in MMR and BMR appears to be linked to membrane FA composition in the skeletal muscle and liver, and (ii) FAs that differ between selected and control lines are involved in pathways that can affect MMR or BMR.ed in pathways that can affect MMR or BMR.)
• Aragones 2009 Cell Metab  + (Aerobic organisms developed mechanisms to … Aerobic organisms developed mechanisms to protect themselves against a shortage of oxygen (O(2)). Recent studies reveal that O(2) sensors, belonging to the novel class of 2-oxoglutarate dependent iron(ii)-dioxygenases, have more important roles in metabolism than anticipated. Here, we provide a "metabolo-centric" overview of the role of the PHD/FIH members of this family in metabolism, in particular on how they regulate O(2) supply and consumption, energy compensation and conservation, O(2) conformance and hypoxia tolerance, redox and pH homeostasis, and other vital metabolic processes with implications in health and disease. These insights may offer novel opportunities for the treatment of ischemic diseases.es for the treatment of ischemic diseases.)
• Pena 2020 Int J Chronic Dis  + (Aerobic training (AT) can support brain he … Aerobic training (AT) can support brain health in Alzheimer’s disease (AD); however, the role of resistance training (RT) in AD is not well established. Aside from direct effects on the brain, exercise may also regulate brain function through secretion of muscle-derived myokines. Aims. This study examined the effects of AT and RT on hippocampal BDNF and IGF-1 signaling, β-amyloid expression, and myokine cathepsin B in the triple transgenic (3xTg-AD) model of AD. 3xTg-AD mice were assigned to one of the following groups: sedentary (Tg), aerobic trained (Tg+AT, 9 wks treadmill running), or resistance trained (Tg+RT, 9 wks weighted ladder climbing) (''N''=10/group). Rotarod latency and strength were assessed pre- and posttraining. Hippocampus and skeletal muscle were collected after training and analyzed by high-resolution respirometry, ELISA, and immunoblotting. Tg+RT showed greater grip strength than Tg and Tg+AT at posttraining (''p''<0.01). Only Tg+AT improved rotarod peak latency (''p''<0.01). Hippocampal IGF-1 concentration was ~15 % greater in Tg+AT and Tg+RT compared to Tg (''p''<0.05); however, downstream signals of p-IGF-1R, p-Akt, p-MAPK, and p-GSK3β were not altered. Cathepsin B, hippocampal p-CREB and BDNF, and hippocampal mitochondrial respiration were not affected by AT or RT. β-Amyloid was ~30 % lower in Tg+RT compared to Tg (''p''<0.05). This data suggests that regular resistance training reduces β-amyloid in the hippocampus concurrent with increased concentrations of IGF-1. Both types of training offered distinct benefits, either by improving physical function or by modifying signals in the hippocampus. Therefore, inclusion of both training modalities may address central defects, as well as peripheral comorbidities in AD.al defects, as well as peripheral comorbidities in AD.)
• Hansen 2022 Free Radic Biol Med  + (Aerobic training can improve vascular endo … Aerobic training can improve vascular endothelial function ''in-vivo''. The aim of this study was to elucidate the mechanisms underlying this improvement in isolated human microvascular endothelial cells. Sedentary males, aged 57 ± 6 years completed 8 weeks of intense aerobic training. Resting muscle biopsies were obtained from the thigh muscle and used for isolation of endothelial cells (pre n = 23, post n = 16). The cells were analyzed for mitochondrial respiration, H₂O₂ emission, glycolysis, protein levels of antioxidants, NADPH oxidase, endothelial nitric oxide (NO) synthase and prostacyclin synthase (PGI₂S). ''In-vivo'' microvascular function, assessed by acetylcholine infusion and arterial blood pressure were also determined. Endothelial mitochondrial respiration and H₂O₂ formation were similar before and after training whereas the expression of superoxide dismutase and the expression of glutathione peroxidase were 2.4-fold (p = 0.012) and 2.3-fold (p = 0.006) higher, respectively, after training. ''In-vivo'' microvascular function was increased by 1.4-fold (p = 0.036) in parallel with a 2.1-fold increase in endothelial PGI₂S expression (p = 0.041). Endothelial cell glycolysis was reduced after training, as indicated by a 65% lower basal production of lactate (p = 0.003) and a 30% lower expression of phosphofructokinase (p = 0.011). Subdivision of the participants according to blood pressure at base-line (n = 23), revealed a 2-fold higher (p = 0.049) rate of H₂O₂ production in endothelial cells from hypertensive participants. Our data show that exercise training increases skeletal muscle microvascular endothelial cell metabolism, antioxidant capacity and the capacity to form prostacyclin. Moreover, elevated blood pressure is associated with increased endothelial mitochondrial ROS formation.the capacity to form prostacyclin. Moreover, elevated blood pressure is associated with increased endothelial mitochondrial ROS formation.)
• DeLany 2014 J Clin Endocrinol Metab  + (African-American women (AAW) have an incre … African-American women (AAW) have an increased risk of developing type 2 diabetes compared to Caucasian women (CW). Lower insulin sensitivity has been reported in AAW, but the reasons for this racial difference and the contributions of liver versus skeletal muscle are incompletely understood.</br></br>We tested the hypothesis that young, non-obese AAW manifest lower insulin sensitivity specific to skeletal muscle, not liver, and is accompanied by lower skeletal muscle mitochondrial oxidative capacity. Participants and Main Outcome Measures: Twenty-two non-obese (BMI 22.7±3.1 kg/m²) AAW and twenty-two matched CW (BMI 22.7±3.1 kg/m²) underwent characterization of body composition, objectively-assessed habitual physical activity, and insulin sensitivity with euglycemic clamps and stable-isotope tracers. Skeletal muscle biopsies were performed for lipid content, fiber-typing, and mitochondrial measurements. </br></br>Peripheral insulin sensitivity was 26% lower in AAW (''p''<0.01), but hepatic insulin sensitivity was similar between groups. Physical activity levels were similar between groups. Lower insulin sensitivity in AAW was not explained by total or central adiposity. Skeletal muscle triglyceride content was similar but mitochondrial content was lower in AAW. Mitochondrial respiration was 24% lower in AAW and correlated with skeletal muscle insulin sensitivity (''r''=0.33, ''p''<0.05).</br>When compared to CW, AAW have similar hepatic insulin sensitivity, but a muscle phenotype characterized by both lower insulin sensitivity and lower mitochondrial oxidative capacity. These observations occur in the absence of obesity and are not explained by physical activity. The only factor associated with lower insulin sensitivity in AAW was mitochondrial oxidative capacity. Because exercise training improves both mitochondrial capacity and insulin sensitivity, we suggest that it may be of particular benefit as a strategy for diabetes prevention in AAW.y be of particular benefit as a strategy for diabetes prevention in AAW.)
• Brooks 2022 J Physiol  + (After a century, it's time to turn the pag … After a century, it's time to turn the page on understanding of lactate metabolism and appreciate that lactate shuttling is an important component of intermediary metabolism in vivo. Cell-cell and intracellular lactate shuttles fulfil purposes of energy substrate production and distribution, as well as cell signalling under fully aerobic conditions. Recognition of lactate shuttling came first in studies of physical exercise where the roles of driver (producer) and recipient (consumer) cells and tissues were obvious. Moreover, the presence of lactate shuttling as part of postprandial glucose disposal and satiety signalling has been recognized. Mitochondrial respiration creates the physiological sink for lactate disposal in vivo. Repeated lactate exposure from regular exercise results in adaptive processes such as mitochondrial biogenesis and other healthful circulatory and neurological characteristics such as improved physical work capacity, metabolic flexibility, learning, and memory. The importance of lactate and lactate shuttling in healthful living is further emphasized when lactate signalling and shuttling are dysregulated as occurs in particular illnesses and injuries. Like a phoenix, lactate has risen to major importance in 21st century biology. major importance in 21st century biology.)
• Ornelas 2017 Cancer Metastasis Rev  + (After more than a century, aspirin remains … After more than a century, aspirin remains one of the most commonly used drugs in western medicine. Although mainly used for its anti-thrombotic, anti-pyretic, and analgesic properties, a multitude of clinical studies have provided convincing evidence that regular, low-dose aspirin use dramatically lowers the risk of cancer. These observations coincide with recent studies showing a functional relationship between platelets and tumors, suggesting that aspirin's chemopreventive properties may result, in part, from direct modulation of platelet biology and biochemistry. Here, we present a review of the biochemistry and pharmacology of aspirin with particular emphasis on its cyclooxygenase-dependent and cyclooxygenase-independent effects in platelets. We also correlate the results of proteomic-based studies of aspirin acetylation in eukaryotic cells with recent developments in platelet proteomics to identify non-cyclooxygenase targets of aspirin-mediated acetylation in platelets that may play a role in its chemopreventive mechanism.y a role in its chemopreventive mechanism.)
• Sumbalova 2022 Abstract Bioblast  + (After overcoming COVID-19, some people dev … After overcoming COVID-19, some people develop a variety of mid- and long-term effects like fatigue, breathlessness, cognitive dysfunction as part of post COVID-19 condition. These symptoms might persist from the initial illness or develop after the recovery. Spa rehabilitation is recommended for patients with post COVID-19 syndrome. In our previous study deficit of CI-linked mitochondrial function and reduced endogenous coenzyme Q₁₀ (CoQ₁₀) concentration was found in platelets of non-hospitalized, non-vaccinated patients 3 – 6 weeks after acute COVID-19 [1].</br></br>In this project we studied effects of mountain spa rehabilitation (MR) and MR combined with ubiquinol (reduced form of CoQ10) supplementation (MRQ) on pulmonary function, clinical and psychological symptoms, endogenous CoQ₁₀ levels, and platelet mitochondrial bioenergetics of patients with post COVID-19 syndrome.</br></br>In total, 36 patients with post COVID-19 syndrome and 15 healthy volunteers (control group) were included in the study. The patients acomplished mountain spa rehabilitation in Sanatorium of Dr. Guhr in Tatranská Polianka, High Tatras, Slovakia with individual therapeutic program including special respiratory physiotherapy procedures, mental well-being, nutrition counseling and adequate exercise therapy. Fourteen patients were on mountain spa rehabilitation (MR) lasting 16 – 18 days and 22 patients were on MR with simultaneous supplementation with ubiquinol (2x100 mg/day) lasting 16 – 18 days and on ubiquinol supplementation for next 12 – 14 days after leaving the spa. Pulmonary function by 6-minute walking test (6MWT), exercise dyspnea by Borg scale (BS), oxygen saturation (SpO₂) and clinical symptoms by questionnaire were evaluated before and after 16 – 18 days of MR. Platelet bioenergetics by high-resolution respirometry, plasma TBARS concentration, and CoQ₁₀ concentration in blood, plasma and platelets were evaluated before (MR1 and MRQ1 groups) and after MR (MR2 and MRQ2 groups), and additionally in 8 patients with CoQ₁₀ supplementation 12 – 14 days after MR (MRQ3 group).</br></br>Platelet mitochondrial Complex I (CI)-linked oxidative phosphorylation (OXPHOS) and electron transfer (ET) capacity was markedly reduced in patients with post COVID-19 syndrome vs the control group (Fig. 1). After 16 – 18 days of MR these parameters improved in both groups vs before MR. The improvement in the group of patients supplemented with ubiquinol was higher than in the non-supplemented group. CI-linked OXPHOS and ET capacity increased further after additional 12 – 14 days of CoQ₁₀ supplementation at home (MRQ3 group).</br></br>The CoQ₁₀ concentration markedly raised after 16 – 18 days of supplementation with ubiquinol in platelets (+60%, p <0.0001), blood (+185%, p<0.0001), and plasma (+232%, p<0.0001) reflecting high bioavailability of supplemented CoQ₁₀. The increase of platelet mitochondrial CI-linked OXPHOS and ET capacity correlated with the increase of CoQ₁₀ in platelets and there was a trend to positive correlation between the improvement of pulmonary function and the increase of CoQ₁₀ in platelets.</br></br>These data show significant role of supplemented ubiquinol in acceleration of mitochondrial health regeneration in patients with post COVID-19 syndrome. Mountain spa rehabilitation with coenzyme Q₁₀ supplementation could be recommended to the patients with post COVID-19 syndrome.</br><small></br># Sumbalová Z, Kucharská J, Palacka P, Rausová Z, Langsjoen P, Langsjoen AM, Gvozdjáková A (2022) Platelet mitochondrial function and endogenous coenzyme Q₁₀ levels are reduced in patients after COVID-19. https://doi.org/10.4149/BLL_2022_002</br># [[SUIT-001 O2 ce-pce D004]]</br></small>4]] </small>)
• Vaupel MiP2010  + (After several decades, the Pasteur-, Crabt … After several decades, the Pasteur-, Crabtree- and [[Warburg effect]]s have experienced a renaissance in current research. The interaction between [[glycolysis]] (i.e., the direct breakdown of glucose to lactate/lactic acid) and mitochondrial [[oxidative phosphorylation]] (i.e., glucose oxidation) was first described by Pasteur in 1857.n) was first described by Pasteur in 1857.)
• Bustamante 2008 Neurochem Res  + (Age related changes in brain cortex NO met … Age related changes in brain cortex NO metabolism were investigated in mitochondria and cytosolic extracts from youth to adulthood. Decreases of 19%, 40% and 71% in NO production were observed in mitochondrial fractions from 3, 7, and 14 months old rats, respectively, as compared with 1-month-old rats. Decreased nNOS protein expression in 14 months old rats was also observed in mitochondria as compared with the nNOS protein expression in 1-month-old rats. Low levels of eNOS protein expression close to the detection limits and no iNOS protein expression were significantly detected in mitochondrial fraction for both groups of age. NO production in the cytosolic extracts also showed a marked decreasing tendency, showing higher levels than those observed in mitochondrial fractions for all groups of age. In the cytosolic extracts, however, the levels were stabilized in adult animals from 7 to 14 months. nNOS protein expression showed a similar age-pattern in cytosolic extracts for both groups of age, while the protein expression pattern for eNOS was higher expressed in adult rats (14 months) than in young animals. As well as in mitochondrial extracts iNOS protein expression was not significantly detected in cytosolic extracts at any age. RT-PCR assays indicated increased levels of nNOS mRNA in 1-month-old rats as compared with 14 months old rats, showing a similar pattern to that one observed for protein nNOS expression. A different aged pattern was observed for eNOS mRNA expression, being lower in 1-month-old rats as compared with 14 months old animals. iNOS mRNA was very low expressed in both groups of age, showing a residual iNOS mRNA that was not significantly detected. State 3 respiration rates were 78% and 85% higher when succinate and malate-glutamate were used as substrates, respectively, in 14 months rats as compared with 1-month-old rats. No changes were observed in state 4 respiration rates. These results could indicate 1 that nNOS and eNOS mRNA and protein expression can be age-dependent, and confirmed the nNOS origin for the mitochondrial NOS. During rat growth, the respiratory function seems to be modulated by NO produced by the different NOS enzymes: nNOS, eNOS and mtNOS present in the cytosol and in the mitochondria.nt in the cytosol and in the mitochondria.)
• Santanasto 2016 Exp Gerontol  + (Age related declines in walking performanc … Age related declines in walking performance may be partly attributable to skeletal muscle mitochondrial dysfunction as mitochondria produce over 90% of ATP needed for movement and the capacity for oxidative phosphorylation decreases with age.</br></br>Participants were from two studies: an ancillary to the Lifestyle Interventions and Independence for Elders (LIFE) Study (n=33), which recruited lower functioning participants (Short Physical Performance Battery [SPPB], 7.8±1.2), and the Study of Energy and Aging-Pilot (SEA, n=29), which enrolled higher functioning (SPPB, 10.8±1.4). Physical activity was measured objectively using the Actigraph accelerometer (LIFE) and SenseWear Pro armband (SEA). Phosphocreatine recovery following muscle contraction of the quadriceps was measured using (31)P magnetic resonance spectroscopy and ATPmax (mM ATP/s) was calculated. Walking performance was defined as time (s) to walk 400m at a usual-pace. The cross-sectional association between mitochondrial function and walking performance was assessed using multivariable linear regression.</br></br>Participants were 77.6±5.3years, 64.2% female and 67.2% white. ATPmax was similar in LIFE vs. SEA (0.52±0.14 vs. 0.55±0.14, p=0.31), despite different function and activity levels (1.6±2.2 vs.77.4±73.3min of moderate activity/day, p<0.01). Higher ATPmax was related to faster walk-time in SEA (r(2)=0.19, p=0.02,); but not the LIFE (r(2)<0.01, p=0.74) cohort.</br></br>Mitochondrial function was associated with walking performance in higher functioning, active older adults, but not lower functioning, sedentary older adults.t not lower functioning, sedentary older adults.)
• Spendiff 2014 Abstract MiP2014  + (Age related loss of independence and mobil … Age related loss of independence and mobility and an ill health are largely associated with sarcopenia, for which a prominent explanation is mitochondrial damage. Increases in mitochondrial DNA (mtDNA) mutations and mitochondrial dysfunction have been reported in aging skeletal muscle [1,2]. Master athletes (MAs) continue training and competing well into old age and represent an prominent model of healthy muscle aging [3]. The cellular mechanisms facilitating this achievement are currently unknown. Given their remarkable aging trajectory, it is reasonable to hypothesize that MAs have superior mitochondrial function and indices of mtDNA integrity. </br></br>15 world class elite MAs and 14 age-sex matched none-athlete controls (NAC), all over the age of 75, underwent muscle MRI scans to assess muscle mass and a biopsy of the vastus lateralis. mtDNA integrity was assessed using the duel cytochrome ''c'' oxidase/succinate dehydrogenase stain to ascertain the number of fibres with a respiratory system defect (RSD) and QPCR to provide an indication of mtDNA deletions and copy number. Three aspects of mitochondrial function were assessed in permeabilized myofibres: ROS production, respiration and calcium retention capacity. </br></br>MAs had significantly more muscle mass than their sedentary counterparts, fewer myofibres with a RSD and an increased mtDNA copy number. However, there were very few differences in any of the three aspects of mitochondrial function examined. Therefore, while MAs have less RSD than NACs at the individual fibre level, this is not sufficient to result in an improvement in mitochondrial function, when studied at the whole muscle level. Thus a superior mitochondrial profile probably does not explain MAs’ remarkable muscle aging trajectory. However, in the presence of age related comorbidities the increased RSD may result in an exacerbation of these conditions in NACs. </br></br>This data raises questions regarding the impact of age related mitochondrial changes on the muscle, as MAs, with the same level of mitochondrial function as controls, still displayed remarkable strength.rols, still displayed remarkable strength.)
• Hashizume 2015 Sci Rep  + (Age-associated accumulation of somatic mut … Age-associated accumulation of somatic mutations in mitochondrial DNA (mtDNA) has been proposed to be responsible for the age-associated mitochondrial respiration defects found in elderly human subjects. We carried out reprogramming of human fibroblast lines derived from elderly subjects by generating their induced pluripotent stem cells (iPSCs), and examined another possibility, namely that these aging phenotypes are controlled not by mutations but by epigenetic regulation. Here, we show that reprogramming of elderly fibroblasts restores age-associated mitochondrial respiration defects, indicating that these aging phenotypes are reversible and are similar to differentiation phenotypes in that both are controlled by epigenetic regulation, not by mutations in either the nuclear or the mitochondrial genome. Microarray screening revealed that epigenetic downregulation of the nuclear-coded GCAT gene, which is involved in glycine production in mitochondria, is partly responsible for these aging phenotypes. Treatment of elderly fibroblasts with glycine effectively prevented the expression of these aging phenotypes. the expression of these aging phenotypes.)
• Bhaskaran 2020 Aging Cell  + (Age-associated loss of muscle mass and fun … Age-associated loss of muscle mass and function (sarcopenia) has a profound effect on the quality of life in the elderly. Our previous studies show that CuZnSOD deletion in mice (Sod1^-/- mice) recapitulates sarcopenia phenotypes, including elevated oxidative stress and accelerated muscle atrophy, weakness, and disruption of neuromuscular junctions (NMJs). To determine whether deletion of Sod1 initiated in neurons in adult mice is sufficient to induce muscle atrophy, we treated young (2- to 4-month-old) Sod1flox/SlickHCre mice with tamoxifen to generate i-mn-Sod1KO mice. CuZnSOD protein was 40-50% lower in neuronal tissue in i-mn-Sod1KO mice. Motor neuron number in ventral spinal cord was reduced 28% at 10 months and more than 50% in 18- to 22-month-old i-mn-Sod1KO mice. By 24 months, 22% of NMJs in i-mn-Sod1KO mice displayed a complete lack of innervation and deficits in specific force that are partially reversed by direct muscle stimulation, supporting the loss of NMJ structure and function. Muscle mass was significantly reduced by 16 months of age and further decreased at 24 months of age. Overall, our findings show that neuronal-specific deletion of CuZnSOD is sufficient to cause motor neuron loss in young mice, but that NMJ disruption, muscle atrophy, and weakness are not evident until past middle age. These results suggest that loss of innervation is critical but may not be sufficient until the muscle reaches a threshold beyond which it cannot compensate for neuronal loss or rescue additional fibers past the maximum size of the motor unit.tional fibers past the maximum size of the motor unit.)
• Bose 2020 Aging Cell  + (Age-associated mitochondrial dysfunction a … Age-associated mitochondrial dysfunction and oxidative damage are primary causes for multiple health problems including sarcopenia and cardiovascular disease (CVD). Though the role of Nrf2, a transcription factor that regulates cytoprotective gene expression, in myopathy remains poorly defined, it has shown beneficial properties in both sarcopenia and CVD. Sulforaphane (SFN), a natural compound Nrf2-related activator of cytoprotective genes, provides protection in several disease states including CVD and is in various stages of clinical trials, from cancer prevention to reducing insulin resistance. This study aimed to determine whether SFN may prevent age-related loss of function in the heart and skeletal muscle. Cohorts of 2-month-old and 21- to 22-month-old mice were administered regular rodent diet or diet supplemented with SFN for 12 weeks. At the completion of the study, skeletal muscle and heart function, mitochondrial function, and Nrf2 activity were measured. Our studies revealed a significant drop in Nrf2 activity and mitochondrial functions, together with a loss of skeletal muscle and cardiac function in the old control mice compared to the younger age group. In the old mice, SFN restored Nrf2 activity, mitochondrial function, cardiac function, exercise capacity, glucose tolerance, and activation/differentiation of skeletal muscle satellite cells. Our results suggest that the age-associated decline in Nrf2 signaling activity and the associated mitochondrial dysfunction might be implicated in the development of age-related disease processes. Therefore, the restoration of Nrf2 activity and endogenous cytoprotective mechanisms by SFN may be a safe and effective strategy to protect against muscle and heart dysfunction due to aging.muscle and heart dysfunction due to aging.)
• Dias 2016 Neurobiol Aging  + (Age-dependent changes in nitric oxide ((•) … Age-dependent changes in nitric oxide ((•)NO) concentration dynamics may play a significant role in both decaying synaptic and metabolic functions in Alzheimer's disease (AD). This neuromodulator acts presynaptically to increase vesicle release and glutamatergic transmission and also regulates mitochondrial function. Under conditions of altered intracellular redox environment, (•)NO may react and produce reactive species such as peroxynitrite. Using the triple transgenic mouse model of AD (3xTgAD), we investigated age-dependent changes in the glutamate-(•)NO axis in the hippocampus. Direct measurement of (•)NO concentration dynamics revealed a significant increase in N-methyl-D-aspartate type receptor-evoked peak (•)NO in the 3xTgAD model at an early age. Aging produced a decrease in peak (•)NO accompanied by significant decrease in production and decay rates in the transgenic model. Evaluation of energy metabolism revealed age-dependent decrease in basal oxygen consumption rate, a general decrease in mitochondrial oxidative phosphorylation parameters, and loss in mitochondrial sparing capacity in both genotypes. Finally, we observed age-dependent increase in 3-nitrotyrosine residues in the hippocampus, consistent with a putative shift in (•)NO bioactivity toward oxidative chemistry associated with neurotoxicity.</br></br>Copyright © 2016 Elsevier Inc. All rights reserved. © 2016 Elsevier Inc. All rights reserved.)
• Gioscia-Ryan 2015 Abstract MiPschool Greenville 2015  + (Age-related arterial endothelial dysfuncti … Age-related arterial endothelial dysfunction, characterized by a decline in endothelium-dependent dilation (EDD), is mediated largely by oxidative stress. Excessive levels of mitochondria-derived reactive oxygen species (mtROS), a hallmark of mitochondrial dysfunction, are an important contributor to tonic arterial oxidative stress-mediated suppression of EDD with aging [1]. In addition to baseline deficits in arterial function, aging may also be accompanied by reduced arterial resilience, i.e., the ability to withstand stress. Aging exacerbates the effects of common stressors such as a “Western”-style (high fat/high sugar) diet, hyperglycemia, and elevated low-density lipoprotein (LDL) cholesterol, such that the age- and stressor-associated impairments in arterial function are compounded [2]. However, whether declines in arterial mitochondrial health contribute to decreased resilience with aging is unknown. Aerobic exercise is a powerful intervention that restores baseline endothelial function with aging and improves mitochondrial health in many non-vascular tissues but the effects of exercise on arterial resilience and mitochondrial health with primary aging are unexplored. We tested the hypothesis that aging would be associated with reduced arterial mitochondrial health and impaired arterial resilience to acute stress, and that voluntary aerobic exercise initiated in late life would improve arterial mitochondrial health and increase resilience of aging arteries. </br></br>Young (5 mo) and old (25 mo) male C57BL/6 mice were randomly assigned to either a sedentary cage control group (young and old control [YC, n=11 and OC, n=12]) or a voluntary aerobic exercise group (young and old voluntary wheel running [YVR, n=10 and OVR, n=11] for 10 weeks. After 10 weeks, endothelial function was assessed in isolated carotid arteries as EDD in response to increasing doses of acetylcholine (ACh). Arterial resilience was determined as the change in EDD response with ACh alone versus following acute application of a mitochondrial stressor (rotenone 0.5 µM, 40 min [1]) or a simulated “Western Diet (WD)” stressor (8 mM glucose + 160 µM palmitate; 40 min intraluminal infusion). The contribution of mtROS to the “WD” stress was determined by assessing EDD with “WD” in the presence of the mitochondria-specific antioxidant MitoQ (1 µM) [3]. Arterial mtROS production was assessed in aortic segments via electron paramagnetic resonance with the mitochondrial superoxide-specific spin probe mitoTEMPO-H. Arterial protein markers of mitochondrial health (PGC-1α, SIRT-3, Fis-1 [TTC11]) were assessed by Western blotting (normalized to GAPDH).by Western blotting (normalized to GAPDH).)