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1
Sandage, Mary J., and Audrey G. Smith. "Muscle Bioenergetic Considerations for Intrinsic Laryngeal Skeletal Muscle Physiology." Journal of Speech, Language, and Hearing Research 60, no. 5 (May 24, 2017): 1254–63. http://dx.doi.org/10.1044/2016_jslhr-s-16-0192.
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PurposeIntrinsic laryngeal skeletal muscle bioenergetics, the means by which muscles produce fuel for muscle metabolism, is an understudied aspect of laryngeal physiology with direct implications for voice habilitation and rehabilitation. The purpose of this review is to describe bioenergetic pathways identified in limb skeletal muscle and introduce bioenergetic physiology as a necessary parameter for theoretical models of laryngeal skeletal muscle function.MethodA comprehensive review of the human intrinsic laryngeal skeletal muscle physiology literature was conducted. Findings regarding intrinsic laryngeal muscle fiber complement and muscle metabolism in human models are summarized and exercise physiology methodology is applied to identify probable bioenergetic pathways used for voice function.ResultsIntrinsic laryngeal skeletal muscle fibers described in human models support the fast, high-intensity physiological requirements of these muscles for biological functions of airway protection. Inclusion of muscle bioenergetic constructs in theoretical modeling of voice training, detraining, fatigue, and voice loading have been limited.ConclusionsMuscle bioenergetics, a key component for muscle training, detraining, and fatigue models in exercise science, is a little-considered aspect of intrinsic laryngeal skeletal muscle physiology. Partnered with knowledge of occupation-specific voice requirements, application of bioenergetics may inform novel considerations for voice habilitation and rehabilitation.
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Cha, Yong-Mei, Petras P. Dzeja, Margaret M. Redfield, Win K. Shen, and Andre Terzic. "Bioenergetic protection of failing atrial and ventricular myocardium by vasopeptidase inhibitor omapatrilat." American Journal of Physiology-Heart and Circulatory Physiology 290, no. 4 (April 2006): H1686—H1692. http://dx.doi.org/10.1152/ajpheart.00384.2005.
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Deficient bioenergetic signaling contributes to myocardial dysfunction and electrical instability in both atrial and ventricular cardiac chambers. Yet, approaches capable to prevent metabolic distress are only partially established. Here, in a canine model of tachycardia-induced congestive heart failure, we compared atrial and ventricular bioenergetics and tested the efficacy of metabolic rescue with the vasopeptidase inhibitor omapatrilat. Despite intrinsic differences in energy metabolism, failing atria and ventricles demonstrated profound bioenergetic deficiency with reduced ATP and creatine phosphate levels and compromised adenylate kinase and creatine kinase catalysis. Depressed phosphotransfer enzyme activities correlated with reduced tissue ATP levels, whereas creatine phosphate inversely related with atrial and ventricular load. Chronic treatment with omapatrilat maintained myocardial ATP, the high-energy currency, and protected adenylate and creatine kinase phosphotransfer capacity. Omapatrilat-induced bioenergetic protection was associated with maintained atrial and ventricular structural integrity, albeit without full recovery of the creatine phosphate pool. Thus therapy with omapatrilat demonstrates the benefit in protecting phosphotransfer enzyme activities and in preventing impairment of atrial and ventricular bioenergetics in heart failure.
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Singh, Dr Deepti. "Principle of Digestion, Metabolism and Bioenergetics in Ayurveda." Journal of Advanced Research in Ayurveda, Yoga, Unani, Sidhha & Homeopathy 4, no. 1&2 (May 31, 2017): 40–45. http://dx.doi.org/10.24321/2394.6547.201710.
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Grimm, Amandine. "Impairments in Brain Bioenergetics in Aging and Tau Pathology: A Chicken and Egg Situation?" Cells 10, no. 10 (September 24, 2021): 2531. http://dx.doi.org/10.3390/cells10102531.
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The brain is the most energy-consuming organ of the body and impairments in brain energy metabolism will affect neuronal functionality and viability. Brain aging is marked by defects in energetic metabolism. Abnormal tau protein is a hallmark of tauopathies, including Alzheimer’s disease (AD). Pathological tau was shown to induce bioenergetic impairments by affecting mitochondrial function. Although it is now clear that mutations in the tau-coding gene lead to tau pathology, the causes of abnormal tau phosphorylation and aggregation in non-familial tauopathies, such as sporadic AD, remain elusive. Strikingly, both tau pathology and brain hypometabolism correlate with cognitive impairments in AD. The aim of this review is to discuss the link between age-related decrease in brain metabolism and tau pathology. In particular, the following points will be discussed: (i) the common bioenergetic features observed during brain aging and tauopathies; (ii) how age-related bioenergetic defects affect tau pathology; (iii) the influence of lifestyle factors known to modulate brain bioenergetics on tau pathology. The findings compiled here suggest that age-related bioenergetic defects may trigger abnormal tau phosphorylation/aggregation and cognitive impairments after passing a pathological threshold. Understanding the effects of aging on brain metabolism may therefore help to identify disease-modifying strategies against tau-induced neurodegeneration.
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Tyrrell, Daniel J., Manish S. Bharadwaj, Matthew J. Jorgensen, Thomas C. Register, Carol Shively, Rachel N. Andrews, Bryan Neth, et al. "Blood-Based Bioenergetic Profiling Reflects Differences in Brain Bioenergetics and Metabolism." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/7317251.
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Blood-based bioenergetic profiling provides a minimally invasive assessment of mitochondrial health shown to be related to key features of aging. Previous studies show that blood cells recapitulate mitochondrial alterations in the central nervous system under pathological conditions, including the development of Alzheimer’s disease. In this study of nonhuman primates, we focus on mitochondrial function and bioenergetic capacity assessed by the respirometric profiling of monocytes, platelets, and frontal cortex mitochondria. Our data indicate that differences in the maximal respiratory capacity of brain mitochondria are reflected by CD14+ monocyte maximal respiratory capacity and platelet and monocyte bioenergetic health index. A subset of nonhuman primates also underwent [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) imaging to assess brain glucose metabolism. Our results indicate that platelet respiratory capacity positively correlates to measures of glucose metabolism in multiple brain regions. Altogether, the results of this study provide early evidence that blood-based bioenergetic profiling is related to brain mitochondrial metabolism. While these measures cannot substitute for direct measures of brain metabolism, provided by measures such as FDG-PET, they may have utility as a metabolic biomarker and screening tool to identify individuals exhibiting systemic bioenergetic decline who may therefore be at risk for the development of neurodegenerative diseases.
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Riddle, Ryan C., and Thomas L. Clemens. "Bone Cell Bioenergetics and Skeletal Energy Homeostasis." Physiological Reviews 97, no. 2 (April 2017): 667–98. http://dx.doi.org/10.1152/physrev.00022.2016.
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The rising incidence of metabolic diseases worldwide has prompted renewed interest in the study of intermediary metabolism and cellular bioenergetics. The application of modern biochemical methods for quantitating fuel substrate metabolism with advanced mouse genetic approaches has greatly increased understanding of the mechanisms that integrate energy metabolism in the whole organism. Examination of the intermediary metabolism of skeletal cells has been sparked by a series of unanticipated observations in genetically modified mice that suggest the existence of novel endocrine pathways through which bone cells communicate their energy status to other centers of metabolic control. The recognition of this expanded role of the skeleton has in turn led to new lines of inquiry directed at defining the fuel requirements and bioenergetic properties of bone cells. This article provides a comprehensive review of historical and contemporary studies on the metabolic properties of bone cells and the mechanisms that control energy substrate utilization and bioenergetics. Special attention is devoted to identifying gaps in our current understanding of this new area of skeletal biology that will require additional research to better define the physiological significance of skeletal cell bioenergetics in human health and disease.
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Acin-Perez, Rebeca, Cristiane Benincá, Byourak Shabane, Orian S. Shirihai, and Linsey Stiles. "Utilization of Human Samples for Assessment of Mitochondrial Bioenergetics: Gold Standards, Limitations, and Future Perspectives." Life 11, no. 9 (September 10, 2021): 949. http://dx.doi.org/10.3390/life11090949.
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Mitochondrial bioenergetic function is a central component of cellular metabolism in health and disease. Mitochondrial oxidative phosphorylation is critical for maintaining energetic homeostasis, and impairment of mitochondrial function underlies the development and progression of metabolic diseases and aging. However, measurement of mitochondrial bioenergetic function can be challenging in human samples due to limitations in the size of the collected sample. Furthermore, the collection of samples from human cohorts is often spread over multiple days and locations, which makes immediate sample processing and bioenergetics analysis challenging. Therefore, sample selection and choice of tests should be carefully considered. Basic research, clinical trials, and mitochondrial disease diagnosis rely primarily on skeletal muscle samples. However, obtaining skeletal muscle biopsies requires an appropriate clinical setting and specialized personnel, making skeletal muscle a less suitable tissue for certain research studies. Circulating white blood cells and platelets offer a promising primary tissue alternative to biopsies for the study of mitochondrial bioenergetics. Recent advances in frozen respirometry protocols combined with the utilization of minimally invasive and non-invasive samples may provide promise for future mitochondrial research studies in humans. Here we review the human samples commonly used for the measurement of mitochondrial bioenergetics with a focus on the advantages and limitations of each sample.
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Castillo, Rodrigo L., Emilio A. Herrera, Alejandro Gonzalez-Candia, Marjorie Reyes-Farias, Nicole de la Jara, Juan Pedro Peña, and Catalina Carrasco-Pozo. "Quercetin Prevents Diastolic Dysfunction Induced by a High-Cholesterol Diet: Role of Oxidative Stress and Bioenergetics in Hyperglycemic Rats." Oxidative Medicine and Cellular Longevity 2018 (2018): 1–14. http://dx.doi.org/10.1155/2018/7239123.
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Alterations in cardiac energy metabolism play a key role in the pathogenesis of diabetic cardiomyopathy. Hypercholesterolemia associated with bioenergetic impairment and oxidative stress has not been well characterized in the cardiac function under glycemic control deficiency conditions. This work aimed to determine the cardioprotective effects of quercetin (QUE) against the damage induced by a high-cholesterol (HC) diet in hyperglycemic rats, addressing intracellular antioxidant mechanisms and bioenergetics. Quercetin reduced HC-induced alterations in the lipid profile and glycemia in rats. In addition, QUE attenuated cardiac diastolic dysfunction (increased E:A ratio), prevented cardiac cholesterol accumulation, and reduced the increase in HC-induced myocyte density. Moreover, QUE reduced HC-induced oxidative stress by preventing the decrease in GSH/GSSG ratio, Nrf2 nuclear translocation, HO-1 expression, and antioxidant enzymatic activity. Quercetin also counteracted HC-induced bioenergetic impairment, preventing a reduction in ATP levels and alterations in PGC-1α, UCP2, and PPARγ expression. In conclusion, the mechanisms that support the cardioprotective effect of QUE in rats with HC might be mediated by the upregulation of antioxidant mechanisms and improved bioenergetics on the heart. Targeting bioenergetics with QUE can be used as a pharmacological approach to modulate structural and functional changes of the heart under hypercholesterolemic and hyperglycemic conditions.
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Keane, Kevin N., Emily K. Calton, Vinicius F. Cruzat, Mario J. Soares, and Philip Newsholme. "The impact of cryopreservation on human peripheral blood leucocyte bioenergetics." Clinical Science 128, no. 10 (March 10, 2015): 723–33. http://dx.doi.org/10.1042/cs20140725.
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Circulating immune cells are considered a source for biomarkers in health and disease, since they are exposed to nutritional, metabolic and immunological stimuli in the vasculature. Cryopreservation of leucocytes is routinely used for long-term storage and determination of phenotypic/functional changes at a later date. Exploring the role of bioenergetics and mitochondrial (dys)function in leucocytes is often examined by using freshly isolated cells. The aim of the pilot study described herein was to assess leucocyte bioenergetics in cryopreserved cells. Leucocytes were isolated from whole blood, counted and frozen in liquid nitrogen (LN2) for a period of 3 months. Cells were thawed at regular intervals and bioenergetic analysis performed using the Seahorse XFe96 flux analyser. Cryogenic storage reduced cell viability by 20%, but cell bioenergetic responses were largely intact for up to 1 month storage in LN2. However, after 1 month storage, mitochondrial function was impaired as reflected by decreasing basal respiration, ATP production, maximum (MAX) respiration, reserve capacity and coupling efficiency. Conversely, glycolytic activity was increased after 1 month, most notably the enhanced glycolytic response to 25 mM glucose without any change in glycolytic capacity. Finally, calculation of bioenergetic health index (BHI) demonstrated that this potential diagnostic parameter was sensitive to cryopreservation. The present study has demonstrated for the first time that cryopreservation of primary immune cells modified their metabolism in a time-dependent fashion, indicated by attenuated aerobic respiration and enhanced glycolytic activity. Taken together, we recommend caution in the interpretation of bioenergetic responses or BHI in cryopreserved samples.
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Hill, Bradford G., Sruti Shiva, Scott Ballinger, Jianhua Zhang, and Victor M. Darley-Usmar. "Bioenergetics and translational metabolism: implications for genetics, physiology and precision medicine." Biological Chemistry 401, no. 1 (December 18, 2019): 3–29. http://dx.doi.org/10.1515/hsz-2019-0268.
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AbstractIt is now becoming clear that human metabolism is extremely plastic and varies substantially between healthy individuals. Understanding the biochemistry that underlies this physiology will enable personalized clinical interventions related to metabolism. Mitochondrial quality control and the detailed mechanisms of mitochondrial energy generation are central to understanding susceptibility to pathologies associated with aging including cancer, cardiac and neurodegenerative diseases. A precision medicine approach is also needed to evaluate the impact of exercise or caloric restriction on health. In this review, we discuss how technical advances in assessing mitochondrial genetics, cellular bioenergetics and metabolomics offer new insights into developing metabolism-based clinical tests and metabolotherapies. We discuss informatics approaches, which can define the bioenergetic-metabolite interactome and how this can help define healthy energetics. We propose that a personalized medicine approach that integrates metabolism and bioenergetics with physiologic parameters is central for understanding the pathophysiology of diseases with a metabolic etiology. New approaches that measure energetics and metabolomics from cells isolated from human blood or tissues can be of diagnostic and prognostic value to precision medicine. This is particularly significant with the development of new metabolotherapies, such as mitochondrial transplantation, which could help treat complex metabolic diseases.
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Srivastava, Rupesh K., Leena Sapra, and Pradyumna K. Mishra. "Osteometabolism: Metabolic Alterations in Bone Pathologies." Cells 11, no. 23 (December 6, 2022): 3943. http://dx.doi.org/10.3390/cells11233943.
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Renewing interest in the study of intermediate metabolism and cellular bioenergetics is brought on by the global increase in the prevalence of metabolic illnesses. Understanding of the mechanisms that integrate energy metabolism in the entire organism has significantly improved with the application of contemporary biochemical tools for quantifying the fuel substrate metabolism with cutting-edge mouse genetic procedures. Several unexpected findings in genetically altered mice have prompted research into the direction of intermediate metabolism of skeletal cells. These findings point to the possibility of novel endocrine connections through which bone cells can convey their energy status to other metabolic control centers. Understanding the expanded function of skeleton system has in turn inspired new lines of research aimed at characterizing the energy needs and bioenergetic characteristics of these bone cells. Bone-forming osteoblast and bone-resorbing osteoclast cells require a constant and large supply of energy substrates such as glucose, fatty acids, glutamine, etc., for their differentiation and functional activity. According to latest research, important developmental signaling pathways in bone cells are connected to bioenergetic programs, which may accommodate variations in energy requirements during their life cycle. The present review article provides a unique perspective of the past and present research in the metabolic characteristics of bone cells along with mechanisms governing energy substrate utilization and bioenergetics. In addition, we discussed the therapeutic inventions which are currently being utilized for the treatment and management of bone-related diseases such as osteoporosis, rheumatoid arthritis (RA), osteogenesis imperfecta (OIM), etc., by modulating the energetics of bone cells. We further emphasized on the role of GUT-associated metabolites (GAMs) such as short-chain fatty acids (SCFAs), medium-chain fatty acids (MCFAs), indole derivates, bile acids, etc., in regulating the energetics of bone cells and their plausible role in maintaining bone health. Emphasis is importantly placed on highlighting knowledge gaps in this novel field of skeletal biology, i.e., “Osteometabolism” (proposed by our group) that need to be further explored to characterize the physiological importance of skeletal cell bioenergetics in the context of human health and bone related metabolic diseases.
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Mancini, Annamaria, Daniela Vitucci, Giuseppe Labruna, Stefania Orrù, and Pasqualina Buono. "Effects of Different Types of Chronic Training on Bioenergetic Profile and Reactive Oxygen Species Production in LHCN-M2 Human Myoblast Cells." International Journal of Molecular Sciences 23, no. 14 (July 6, 2022): 7491. http://dx.doi.org/10.3390/ijms23147491.
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Human skeletal muscle contains three different types of fibers, each with a different metabolism. Exercise differently contributes to differentiation and metabolism in human myoblast cells. The aims of the present study were to investigate the effects of different types of chronic training on the human LHCN-M2 myoblast cell bioenergetic profile during differentiation in real time and on the ROS overproduction consequent to H2O2 injury. We demonstrated that exercise differently affects the myoblast bioenergetics: aerobic exercise induced the most efficient glycolytic and oxidative capacity and proton leak reduction compared to untrained or anaerobic trained sera-treated cells. Similarly, ROS overproduction after H2O2 stress was lower in cells treated with differently trained sera compared to untrained sera, indicating a cytoprotective effect of training on the reduction of oxidative stress, and thus the promotion of longevity. In conclusion, for the first time, this study has provided knowledge regarding the modifications induced by different types of chronic training on human myoblast cell bioenergetics during the differentiation process in real time, and on ROS overproduction due to stress, with positive implications in terms of longevity.
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Mishra, Prashant, and David C. Chan. "Metabolic regulation of mitochondrial dynamics." Journal of Cell Biology 212, no. 4 (February 8, 2016): 379–87. http://dx.doi.org/10.1083/jcb.201511036.
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Mitochondria are renowned for their central bioenergetic role in eukaryotic cells, where they act as powerhouses to generate adenosine triphosphate from oxidation of nutrients. At the same time, these organelles are highly dynamic and undergo fusion, fission, transport, and degradation. Each of these dynamic processes is critical for maintaining a healthy mitochondrial population. Given the central metabolic function of mitochondria, it is not surprising that mitochondrial dynamics and bioenergetics reciprocally influence each other. We review the dynamic properties of mitochondria, with an emphasis on how these processes respond to cellular signaling events and how they affect metabolism.
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Serbulea, Vlad, Clint M. Upchurch, Michael S. Schappe, Paxton Voigt, Dory E. DeWeese, Bimal N. Desai, Akshaya K. Meher, and Norbert Leitinger. "Macrophage phenotype and bioenergetics are controlled by oxidized phospholipids identified in lean and obese adipose tissue." Proceedings of the National Academy of Sciences 115, no. 27 (June 11, 2018): E6254—E6263. http://dx.doi.org/10.1073/pnas.1800544115.
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Adipose tissue macrophages (ATMs) adapt their metabolic phenotype either to maintain lean tissue homeostasis or drive inflammation and insulin resistance in obesity. However, the factors in the adipose tissue microenvironment that control ATM phenotypic polarization and bioenergetics remain unknown. We have recently shown that oxidized phospholipids (OxPL) uniquely regulate gene expression and cellular metabolism in Mox macrophages, but the presence of the Mox phenotype in adipose tissue has not been reported. Here we show, using extracellular flux analysis, that ATMs isolated from lean mice are metabolically inhibited. We identify a unique population of CX3CR1neg/F4/80low ATMs that resemble the Mox (Txnrd1+HO1+) phenotype to be the predominant ATM phenotype in lean adipose tissue. In contrast, ATMs isolated from obese mice had characteristics typical of the M1/M2 (CD11c+CD206+) phenotype with highly activated bioenergetics. Quantifying individual OxPL species in the stromal vascular fraction of murine adipose tissue, using targeted liquid chromatography-mass spectrometry, revealed that high fat diet-induced adipose tissue expansion led to a disproportional increase in full-length over truncated OxPL species. In vitro studies showed that macrophages respond to truncated OxPL species by suppressing bioenergetics and up-regulating antioxidant programs, mimicking the Mox phenotype of ATMs isolated from lean mice. Conversely, full-length OxPL species induce proinflammatory gene expression and an activated bioenergetic profile that mimics ATMs isolated from obese mice. Together, these data identify a redox-regulatory Mox macrophage phenotype to be predominant in lean adipose tissue and demonstrate that individual OxPL species that accumulate in adipose tissue instruct ATMs to adapt their phenotype and bioenergetic profile to either maintain redox homeostasis or to promote inflammation.
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Pacelli, Consiglia, Giovannina Rotundo, Lucia Lecce, Marta Menga, Eris Bidollari, Rosella Scrima, Olga Cela, et al. "Parkin Mutation Affects Clock Gene-Dependent Energy Metabolism." International Journal of Molecular Sciences 20, no. 11 (June 5, 2019): 2772. http://dx.doi.org/10.3390/ijms20112772.
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Growing evidence highlights a tight connection between circadian rhythms, molecular clockworks, and mitochondrial function. In particular, mitochondrial quality control and bioenergetics have been proven to undergo circadian oscillations driven by core clock genes. Parkinson’s disease (PD) is a chronic neurodegenerative disease characterized by a selective loss of dopaminergic neurons. Almost half of the autosomal recessive forms of juvenile parkinsonism have been associated with mutations in the PARK2 gene coding for parkin, shown to be involved in mitophagy-mediated mitochondrial quality control. The aim of this study was to investigate, in fibroblasts from genetic PD patients carrying parkin mutations, the interplay between mitochondrial bioenergetics and the cell autonomous circadian clock. Using two different in vitro synchronization protocols, we demonstrated that normal fibroblasts displayed rhythmic oscillations of both mitochondrial respiration and glycolytic activity. Conversely, in fibroblasts obtained from PD patients, a severe damping of the bioenergetic oscillatory patterns was observed. Analysis of the core clock genes showed deregulation of their expression patterns in PD fibroblasts, which was confirmed in induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs) derived thereof. The results from this study support a reciprocal interplay between the clockwork machinery and mitochondrial energy metabolism, point to a parkin-dependent mechanism of regulation, and unveil a hitherto unappreciated level of complexity in the pathophysiology of PD and eventually other neurodegenerative diseases.
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Silvestre, Isabel Barao, Raul Y. Dagda, Ruben K. Dagda, and Victor Darley-Usmar. "Mitochondrial alterations in NK lymphocytes from ME/CFS patients." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 126.39. http://dx.doi.org/10.4049/jimmunol.202.supp.126.39.
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Abstract Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by profound fatigue, flu-like symptoms, trouble concentrating, and autonomic problems, all of which worsen after exertion. ME/CFS patients have impaired natural killer (NK) cell activity. NK lymphocytes are a critical first defense against viruses and cancer. ME/CFS patients have difficulties controlling viral infections and many develop non-Hodgkin’s lymphoma. Mitochondrial metabolism is crucial for immune cell function. Mitochondria dysfunction has been previously reported in ME/CFS, but it is not known whether the NK cells of these patients have altered mitochondrial metabolism that affect their activity and contribute to ME/CFS pathogenesis. More importantly, there is currently no efficient method to diagnose ME/CFS or assess efficacy of therapeutic interventions. The Bioenergetic Health Index (BHI) has been developed as promising and reliable surrogate readout of human health by measuring the bioenergetic status of immune cells. Variations in bioenergetic function in patient’s immune cells can reflect both metabolic stress and the mutable role of these cells in ME/CFS immunity and pathogenesis. In our study, we observed that the two main energy-generating mitochondrial pathways, oxidative phosphorylation and glycolysis (bioenergetics parameters), are deregulated in ME/CFS NK cells and in PBMCs. Moreover, we observed alterations in the morphology and membrane potential of the mitochondria of NK cells. These mitochondrial features can affect NK cell function and contribute to the severity of disease. To date, this is the first metabolism assessment of NK cells in ME/CFS and as potential new diagnostic tool for the disease.
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Bettinazzi, Stefano, Liliana Milani, Pierre U. Blier, and Sophie Breton. "Bioenergetic consequences of sex-specific mitochondrial DNA evolution." Proceedings of the Royal Society B: Biological Sciences 288, no. 1957 (August 18, 2021): 20211585. http://dx.doi.org/10.1098/rspb.2021.1585.
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Doubly uniparental inheritance (DUI) represents a notable exception to the general rule of strict maternal inheritance (SMI) of mitochondria in metazoans. This system entails the coexistence of two mitochondrial lineages (F- and M-type) transmitted separately through oocytes and sperm, thence providing an unprecedented opportunity for the mitochondrial genome to evolve adaptively for male functions. In this study, we explored the impact of a sex-specific mitochondrial evolution upon gamete bioenergetics of DUI and SMI bivalve species, comparing the activity of key enzymes of glycolysis, fermentation, fatty acid metabolism, tricarboxylic acid cycle, oxidative phosphorylation and antioxidant metabolism. Our findings suggest reorganized bioenergetic pathways in DUI gametes compared to SMI gametes. This generally results in a decreased enzymatic capacity in DUI sperm with respect to DUI oocytes, a limitation especially prominent at the terminus of the electron transport system. This bioenergetic remodelling fits a reproductive strategy that does not require high energy input and could potentially link with the preservation of the paternally transmitted mitochondrial genome in DUI species. Whether this phenotype may derive from positive or relaxed selection acting on DUI sperm is still uncertain.
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Fan, Yang-Yi, Laurie A. Davidson, Evelyn S. Callaway, Gus A. Wright, Stephen Safe, and Robert S. Chapkin. "A bioassay to measure energy metabolism in mouse colonic crypts, organoids, and sorted stem cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 309, no. 1 (July 1, 2015): G1—G9. http://dx.doi.org/10.1152/ajpgi.00052.2015.
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Evidence suggests that targeting cancer cell energy metabolism might be an effective therapeutic approach for selective ablation of malignancies. Using a Seahorse Extracellular Flux Analyzer, we have demonstrated that select environmental agents can alter colonic mitochondrial function by increasing respiration-induced proton leak, thereby inducing apoptosis, a marker of colon cancer risk. To further probe bioenergetics in primary intestinal cells, we developed methodology that can be modified and adapted to measure the bioenergetic profiles of colonic crypts, the basic functional unit of the colon, and colonic organoids, an ex vivo 3D culture of colonic crypts. Furthermore, in combination with the MoFlo Astrios High-Speed Cell Sorter, we were able to measure the bioenergetic profiles of colonic adult stem and daughter cells from Lgr5-EGFP-IRES-creERT2 transgenic mice. We examined the effects of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD), a full arylhydrocarbon receptor agonist, known to affect gastrointestinal function and cancer risk, on the bioenergetic profiles of intestinal epithelial cells. Mouse colonic crypts, organoids, or sorted single cells were seeded onto Matrigel-precoated Seahorse XF24 microplates for extracellular flux analysis. Temporal analyses revealed distinct energy metabolic profiles in crypts and organoids challenged with TCDD. Furthermore, sorted Lgr5+ stem cells exhibited a Warburg-like metabolic profile. This is noteworthy because perturbations in stem cell dynamics are generally believed to represent the earliest step toward colon tumorigenesis. We propose that our innovative methodology may facilitate future in vivo/ex vivo metabolic studies using environmental agents affecting colonocyte energy metabolism.
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Gevezova, Maria, Danail Minchev, Iliana Pacheva, Yordan Sbirkov, Ralitsa Yordanova, Elena Timova, Vasil Kotetarov, Ivan Ivanov, and Victoria Sarafian. "Cellular Bioenergetic and Metabolic Changes in Patients with Autism Spectrum Disorder." Current Topics in Medicinal Chemistry 21, no. 11 (August 4, 2021): 985–94. http://dx.doi.org/10.2174/1568026621666210521142131.
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Background: Although Autism Spectrum Disorder (ASD) is considered a heterogeneous neurological disease in childhood, a growing body of evidence associates it with mitochondrial dysfunction explaining the observed comorbidities. Introduction: The aim of this study is to identify variations in cellular bioenergetics and metabolism dependent on mitochondrial function in ASD patients and healthy controls using Peripheral Blood Mononuclear Cells (PBMCs). We hypothesized that PBMCs may reveal the cellular pathology and provide evidence of bioenergetic and metabolic changes accompanying the disease. Method: PBMC from children with ASD and a control group of the same age and gender were isolated. All patients underwent an in-depth clinical evaluation. A well-characterized cohort of Bulgarian children is selected. Bioenergetic and metabolic studies of isolated PBMCs are performed with a Seahorse XFp analyzer. Result: Our data show that PBMCs from patients with ASD have increased respiratory reserve capacity (by 27.5%), increased maximal respiration (by 67%) and altered adaptive response to oxidative stress induced by DMNQ. In addition, we demonstrate а strong dependence on fatty acids and impaired ability to reprogram cell metabolism. The listed characteristics are not observed in the control group. These results can contribute to a better understanding of the underlying causes of ASD, which is crucial for selecting a successful treatment. Conclusion: The current study, for the first time, provides a functional analysis of cell bioenergetics and metabolic changes in a group of Bulgarian patients with ASD. It reveals physiological abnormalities that do not allow mitochondria to adapt and meet the increased energetic requirements of the cell. The link between mitochondria and ASD is not yet fully understood, but this may lead to the discovery of new approaches for nutrition and therapy.
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Rendon, D. A. "Mitochondrial Bioenergetics after Nine-Day Treatment Regimen with Benzonidazole in Rats." International Journal of Toxicology 26, no. 6 (November 2007): 571–75. http://dx.doi.org/10.1080/10915810701728698.
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The bioenergetics of cardiac, liver, and kidney mitochondria after 9-day treatment regimen with benzonidazole was studied in rats. The drug was given by oral gavage to adult male Sprague-Dawley rats for 9 consecutive days (100 mg benzonidazole/kg body weight as daily dose). The assayed mitochondrial bioenergetic parameters were the state 4, state 3, respiratory control, efficiency of oxidative phosphorylation, and the activity of the mitochondrial ATP synthase. The results showed that mitochondrial parameters were not altered statistically after in cardiac and kidney mitochondria, but respiratory control in liver mitochondria was statistically increased with benzonidazole treatment. This change was likely due to a slight decrease in state 4 bioenergy metabolism. These results indicate that 9-day benzonidazole treatment regimen had no negative effect on cardiac, liver, and kidney mitochondrial energy metabolism but increased respiratory control in rat liver mitochondria.
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Bottoni, Patrizia, Alessandro Pontoglio, Salvatore Scarà, Luisa Pieroni, Andrea Urbani, and Roberto Scatena. "Mitochondrial Respiratory Complexes as Targets of Drugs: The PPAR Agonist Example." Cells 11, no. 7 (March 30, 2022): 1169. http://dx.doi.org/10.3390/cells11071169.
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Mitochondrial bioenergetics are progressively acquiring significant pathophysiological roles. Specifically, mitochondria in general and Electron Respiratory Chain in particular are gaining importance as unintentional targets of different drugs. The so-called PPAR ligands are a class of drugs which not only link and activate Peroxisome Proliferator-Activated Receptors but also show a myriad of extrareceptorial activities as well. In particular, they were shown to inhibit NADH coenzyme Q reductase. However, the molecular picture of this intriguing bioenergetic derangement has not yet been well defined. Using high resolution respirometry, both in permeabilized and intact HepG2 cells, and a proteomic approach, the mitochondrial bioenergetic damage induced by various PPAR ligands was evaluated. Results show a derangement of mitochondrial oxidative metabolism more complex than one related to a simple perturbation of complex I. In fact, a partial inhibition of mitochondrial NADH oxidation seems to be associated not only with hampered ATP synthesis but also with a significant reduction in respiratory control ratio, spare respiratory capacity, coupling efficiency and, last but not least, serious oxidative stress and structural damage to mitochondria.
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Bafiti, Vivi, Sotiris Ouzounis, Eleni Siapi, Ioanna Maria Grypari, Andreas Theofanopoulos, Vasilios Panagiotopoulos, Vasiliki Zolota, Dimitrios Kardamakis, and Theodora Katsila. "Bioenergetic Profiling in Glioblastoma Multiforme Patients with Different Clinical Outcomes." Metabolites 13, no. 3 (February 28, 2023): 362. http://dx.doi.org/10.3390/metabo13030362.
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The accumulation of cell biomass is associated with dramatically increased bioenergetic and biosynthetic demand. Metabolic reprogramming, once thought as an epiphenomenon, currently relates to disease progression, also in response to extracellular fate-decisive signals. Glioblastoma multiforme patients often suffer misdiagnosis, short survival time, low quality of life, and poor disease management options. Today, tumor genetic testing and histological analysis guide diagnosis and treatment. We and others appreciate that metabolites complement translational biomarkers and molecular signatures in disease profiling and phenotyping. Herein, we coupled a mixed-methods content analysis to a mass spectrometry-based untargeted metabolomic analysis on plasma samples from glioblastoma multiforme patients to delineate the role of metabolic remodeling in biological plasticity and, hence, disease severity. Following data processing and analysis, we established a bioenergetic profile coordinated by the mitochondrial function and redox state, lipids, and energy substrates. Our findings show that epigenetic modulators are key players in glioblastoma multiforme cell metabolism, in particular when microRNAs are considered. We propose that biological plasticity in glioblastoma multiforme is a mechanism of adaptation and resistance to treatment which is eloquently revealed by bioenergetics.
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Nesbeth, Paula-Dene, Thomas Ziegler, Daiana Weiss, Li Hao, Matthew Smith, Dean Jones, M. Neale Weitzmann, and Jessica Alvarez. "Linoleic Acid Reduces Oxidative Phosphorylation and Impairs Early Differentiation of MC3T3-E1 Osteoblast Precursor Cells." Current Developments in Nutrition 6, Supplement_1 (June 2022): 452. http://dx.doi.org/10.1093/cdn/nzac057.018.
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Abstract Objectives Untargeted metabolomics analyses by our group have shown that plasma linoleic acid (LA) was inversely associated with bone mineral density Z-score and that bone formation indices were associated with energy-generating metabolic pathways, including fatty acid b-oxidation, in adult cohorts. Here, we examined the effect of increasing LA concentrations on osteoblast precursor cell bioenergetics and osteoblast differentiation to determine whether high LA is detrimental to bone formation. Methods We treated MC3T3-E1 pre-osteoblastic cells with 0 µM (control), 1 μM, and 50 μM LA cultured in osteogenic differentiation media supplemented with 50 µM L-ascorbic acid and 2 mM β-glycerophosphate. To assess the effect of LA on early commitment/differentiation, cells were stained for alkaline phosphatase activity and late differentiation using Alizarin Red S staining for mineral deposition, at 7 and 18 days, respectively. To assess cellular bioenergetics, real-time ATP production rates in LA treated (1 or 50 μM) and control MC3T3-E1 cells were measured using an extracellular flux analyzer after 24 hours (normalized for total protein content). Differences in bioenergetic values were determined using one-way ANOVA or Kruskal-Wallis test with Tukey's HSD or Dunn's post hoc tests. Results While LA had no effect on late differentiation/mineralizing activity of MC3T3 cells, LA dose-dependently decreased commitment/early differentiation. LA also significantly altered the bioenergetic profile of MC3T3-E1 cells by decreasing basal oxygen consumption rate (P < 0.001), as well as mitochondrial and total ATP production rate (P < 0.05 and P < 0.001, respectively). There were no significant changes in glycolytic ATP production rate. Conclusions Osteoblast differentiation is a highly bioenergetic process, and this study suggests excess LA may impair ATP production from oxidative phosphorylation. This, in turn, may impede commitment and early differentiation of osteoblasts. Our study supports further clinical and translational investigation into the role of LA and energy metabolism in osteoblast function, as well as bone formation. Funding Sources National Institutes of Health.
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Bloise, Flavia F., Aline Cordeiro, and Tania Maria Ortiga-Carvalho. "Role of thyroid hormone in skeletal muscle physiology." Journal of Endocrinology 236, no. 1 (January 2018): R57—R68. http://dx.doi.org/10.1530/joe-16-0611.
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Thyroid hormones (TH) are crucial for development, growth, differentiation, metabolism and thermogenesis. Skeletal muscle (SM) contractile function, myogenesis and bioenergetic metabolism are influenced by TH. These effects depend on the presence of the TH transporters MCT8 and MCT10 in the plasma membrane, the expression of TH receptors (THRA or THRB) and hormone availability, which is determined either by the activation of thyroxine (T4) into triiodothyronine (T3) by type 2 iodothyronine deiodinases (D2) or by the inactivation of T4 into reverse T3 by deiodinases type 3 (D3). SM relaxation and contraction rates depend on T3 regulation of myosin expression and energy supplied by substrate oxidation in the mitochondria. The balance between D2 and D3 expression determines TH intracellular levels and thus influences the proliferation and differentiation of satellite cells, indicating an important role of TH in muscle repair and myogenesis. During critical illness, changes in TH levels and in THR and deiodinase expression negatively affect SM function and repair. This review will discuss the influence of TH action on SM contraction, bioenergetics metabolism, myogenesis and repair in health and illness conditions.
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Lee, Seong-il, Janneke G. J. Hoeijmakers, Catharina G. Faber, Ingemar S. J. Merkies, Giuseppe Lauria, and Stephen G. Waxman. "The small fiber neuropathy NaV1.7 I228M mutation: impaired neurite integrity via bioenergetic and mitotoxic mechanisms, and protection by dexpramipexole." Journal of Neurophysiology 123, no. 2 (February 1, 2020): 645–57. http://dx.doi.org/10.1152/jn.00360.2019.
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Gain-of-function variants in voltage-gated sodium channel NaV1.7 that increase firing frequency and spontaneous firing of dorsal root ganglion (DRG) neurons have recently been identified in 5–10% of patients with idiopathic small fiber neuropathy (I-SFN). Our previous in vitro observations suggest that enhanced sodium channel activity can contribute to a decrease in length of peripheral sensory axons. We have hypothesized that sustained sodium influx due to the expression of SFN-associated sodium channel variants may trigger an energetic deficit in neurons that contributes to degeneration and loss of nerve fibers in SFN. Using an ATP FRET biosensor, we now demonstrate reduced steady-state levels of ATP and markedly faster ATP decay in response to membrane depolarization in cultured DRG neurons expressing an SFN-associated variant NaV1.7, I228M, compared with wild-type neurons. We also observed that I228M neurons show a significant reduction in mitochondrial density and size, indicating dysfunctional mitochondria and a reduced bioenergetic capacity. Finally, we report that exposure to dexpramipexole, a drug that improves mitochondrial energy metabolism, increases the neurite length of I228M-expressing neurons. Our data suggest that expression of gain-of-function variants of NaV1.7 can damage mitochondria and compromise cellular capacity for ATP production. The resulting bioenergetic crisis can consequently contribute to loss of axons in SFN. We suggest that, in addition to interventions that reduce ionic disturbance caused by mutant NaV1.7 channels, an alternative therapeutic strategy might target the bioenergetic burden and mitochondrial damage that occur in SFN associated with NaV1.7 gain-of-function mutations. NEW & NOTEWORTHY Sodium channel NaV1.7 mutations that increase dorsal root ganglion (DRG) neuron excitability have been identified in small fiber neuropathy (SFN). We demonstrate reduced steady-state ATP levels, faster depolarization-evoked ATP decay, and reduced mitochondrial density and size in cultured DRG neurons expressing SFN-associated variant NaV1.7 I228M. Dexpramipexole, which improves mitochondrial energy metabolism, has a protective effect. Because gain-of-function NaV1.7 variants can compromise bioenergetics, therapeutic strategies that target bioenergetic burden and mitochondrial damage merit study in SFN.
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Chang, Jan-Gowth, Ni Tien, Yi-Chih Chang, Meng-Liang Lin, and Shih-Shun Chen. "Oxidative Stress-Induced Unscheduled CDK1–Cyclin B1 Activity Impairs ER–Mitochondria-Mediated Bioenergetic Metabolism." Cells 10, no. 6 (May 21, 2021): 1280. http://dx.doi.org/10.3390/cells10061280.
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Targeting the activities of endoplasmic reticulum (ER)–mitochondrial-dependent metabolic reprogramming is considered one of the most promising strategies for cancer treatment. Here, we present biochemical subcellular fractionation, coimmunoprecipitation, gene manipulation, and pharmacologic evidence that induction of mitochondria-localized phospho (p)-cyclin dependent kinase 1 (CDK1) (Thr 161)–cyclin B1 complexes by apigenin in nasopharyngeal carcinoma (NPC) cells impairs the ER–mitochondrial bioenergetics and redox regulation of calcium (Ca++) homeostasis through suppressing the B cell lymphoma 2 (BCL-2)/BCL-2/B-cell lymphoma-extra large (BCL-xL)-modulated anti-apoptotic and metabolic functions. Using a specific inducer, inhibitor, or short hairpin RNA for acid sphingomyelinase (ASM) demonstrated that enhanced lipid raft-associated ASM activity confers alteration of the lipid composition of lipid raft membranes, which leads to perturbation of protein trafficking, and induces formation of p110α free p85α–unphosphorylated phosphatase and tensin homolog deleted from chromosome 10 complexes in the lipid raft membranes, causing disruption of phosphatidylinositol 3-kinase (PI3K)−protein kinase B (Akt)−GTP-ras-related C3 botulinum toxin substrate 1 (Rac1)-mediated signaling, thus triggering the p-CDK1 (Thr 161))–cyclin B1-mediated BCL-2 (Thr 69/Ser 87)/BCL-xL (Ser 62) phosphorylation and accompanying impairment of ER–mitochondria-regulated bioenergetic, redox, and Ca++ homeostasis. Inhibition of apigenin-induced reactive oxygen species (ROS) generation by a ROS scavenger N-acetyl-L-cysteine blocked the lipid raft membrane localization and activation of ASM and formation of ceramide-enriched lipid raft membranes, returned PI3K−Akt−GTP-Rac1-modulated CDK1–cyclin B1 activity, and subsequently restored the BCL-2/BCL-xL-regulated ER–mitochondrial bioenergetic activity. Thus, this study reveals a novel molecular mechanism of the pro-apoptotic activity of ASM controlled by oxidative stress to modulate the ER–mitochondrial bioenergetic metabolism, as well as suggests the disruption of CDK1–cyclin B1-mediated BCL-2/BCL-xL oncogenic activity by triggering oxidative stress−ASM-induced PI3K−Akt−GTP-Rac1 inactivation as a therapeutic approach for NPC.
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Bengsch, Bertram R., Andy L. Johnson, Makoto Kurachi, Pamela Odorizzi, Kristen E. Pauken, John Attanasio, and E. John Wherry. "Early onset and persistence of metabolic alterations in exhausted T cells is regulated by PD-1." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 61.15. http://dx.doi.org/10.4049/jimmunol.196.supp.61.15.
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Abstract Dynamic reprogramming of metabolism is essential for T cell effector function and formation of memory. However, regulation of cellular metabolism in exhausted T cells in chronic infections and cancer is poorly understood. Here we found that as early as the first week of chronic LCMV infection, before severe T cell dysfunction becomes established, virus-specific CD8 T cells are already unable to match the bioenergetic demands of effector CD8 T cells generated during acutely resolving LCMV infection. Suppression of T cells bioenergetics involves restriction of glucose uptake and utilization, despite the up-regulation of multiple other metabolic pathways. The inhibitory receptor PD-1 controlled the development of this early glycolytic defect as well as mitochondrial mass and quality in the presence of persisting mTOR signaling. The suppression of glycolysis and mitochondrial metabolism in exhausted T cells persists into established chronic infection. Therapeutic reinvigoration of exhausted T cells by PD-L1 blockade reprogrammed the metabolism of PD-1Int but not the terminal PD-1Hi subset of exhausted T cells. These data highlight a key metabolic control event early in T cell exhaustion that precedes major transcriptional changes. Our findings also suggest that manipulating metabolism in combination with checkpoint blockade may enhance therapeutic outcomes.
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Miotto, Paula M., Chris McGlory, Tanya M. Holloway, Stuart M. Phillips, and Graham P. Holloway. "Sex differences in mitochondrial respiratory function in human skeletal muscle." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 314, no. 6 (June 1, 2018): R909—R915. http://dx.doi.org/10.1152/ajpregu.00025.2018.
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Mitochondrial bioenergetic contributions to sex differences in human skeletal muscle metabolism remain poorly defined. The primary aim of this study was to determine whether mitochondrial respiratory kinetics differed between healthy young men and women in permeabilized skeletal muscle fibers. While men and women displayed similar ( P > 0.05) maximal respiration rates and abundance of mitochondrial/adenosine diphosphate (ADP) transport proteins, women had lower ( P < 0.05) mitochondrial ADP sensitivity (+30% apparent Km) and absolute respiration rates at a physiologically relevant ADP concentration (100 μM). Moreover, although men and women exhibited similar carnitine palmitoyl transferase-I protein content- and palmitoyl-CoA-supported respiration, women displayed greater sensitivity to malonyl-CoA-mediated respiratory inhibition. These data establish baseline sex differences in mitochondrial bioenergetics and provide the foundation for studying mitochondrial function within the context of metabolic perturbations and diseases that affect men and women differently.
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Hutfles, Lewis J., Heather M. Wilkins, Scott J. Koppel, Ian W. Weidling, J. Eva Selfridge, Eephie Tan, John P. Thyfault, et al. "A bioenergetics systems evaluation of ketogenic diet liver effects." Applied Physiology, Nutrition, and Metabolism 42, no. 9 (September 2017): 955–62. http://dx.doi.org/10.1139/apnm-2017-0068.
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Ketogenic diets induce hepatocyte fatty acid oxidation and ketone body production. To further evaluate how ketogenic diets affect hepatocyte bioenergetic infrastructure, we analyzed livers from C57Bl/6J male mice maintained for 1 month on a ketogenic or standard chow diet. Compared with the standard diet, the ketogenic diet increased cytosolic and mitochondrial protein acetylation and also altered protein succinylation patterns. SIRT3 protein decreased while SIRT5 protein increased, and gluconeogenesis, oxidative phosphorylation, and mitochondrial biogenesis pathway proteins were variably and likely strategically altered. The pattern of changes observed can be used to inform a broader systems overview of how ketogenic diets affect liver bioenergetics.
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Ciccarone, Fabio, Luca Di Leo, Giacomo Lazzarino, Giuseppe Maulucci, Flavio Di Giacinto, Barbara Tavazzi, and Maria Rosa Ciriolo. "Aconitase 2 inhibits the proliferation of MCF-7 cells promoting mitochondrial oxidative metabolism and ROS/FoxO1-mediated autophagic response." British Journal of Cancer 122, no. 2 (December 10, 2019): 182–93. http://dx.doi.org/10.1038/s41416-019-0641-0.
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Abstract Background Deregulation of the tricarboxylic acid cycle (TCA) due to mutations in specific enzymes or defective aerobic metabolism is associated with tumour growth. Aconitase 2 (ACO2) participates in the TCA cycle by converting citrate to isocitrate, but no evident demonstrations of its involvement in cancer metabolism have been provided so far. Methods Biochemical assays coupled with molecular biology, in silico, and cellular tools were applied to circumstantiate the impact of ACO2 in the breast cancer cell line MCF-7 metabolism. Fluorescence lifetime imaging microscopy (FLIM) of NADH was used to corroborate the changes in bioenergetics. Results We showed that ACO2 levels are decreased in breast cancer cell lines and human tumour biopsies. We generated ACO2- overexpressing MCF-7 cells and employed comparative analyses to identify metabolic adaptations. We found that increased ACO2 expression impairs cell proliferation and commits cells to redirect pyruvate to mitochondria, which weakens Warburg-like bioenergetic features. We also demonstrated that the enhancement of oxidative metabolism was supported by mitochondrial biogenesis and FoxO1-mediated autophagy/mitophagy that sustains the increased ROS burst. Conclusions This work identifies ACO2 as a relevant gene in cancer metabolic rewiring of MCF-7 cells, promoting a different utilisation of pyruvate and revealing the potential metabolic vulnerability of ACO2-associated malignancies.
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Bouillaud, Frédéric, and Claire Pecqueur. "UCP2 bioenergetics and metabolism." Biochimica et Biophysica Acta (BBA) - Bioenergetics 1797 (July 2010): 84. http://dx.doi.org/10.1016/j.bbabio.2010.04.252.
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Puurand, Marju, Kersti Tepp, Natalja Timohhina, Jekaterina Aid, Igor Shevchuk, Vladimir Chekulayev, and Tuuli Kaambre. "Tubulin βII and βIII Isoforms as the Regulators of VDAC Channel Permeability in Health and Disease." Cells 8, no. 3 (March 13, 2019): 239. http://dx.doi.org/10.3390/cells8030239.
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In recent decades, there have been several models describing the relationships between the cytoskeleton and the bioenergetic function of the cell. The main player in these models is the voltage-dependent anion channel (VDAC), located in the mitochondrial outer membrane. Most metabolites including respiratory substrates, ADP, and Pi enter mitochondria only through VDAC. At the same time, high-energy phosphates are channeled out and directed to cellular energy transfer networks. Regulation of these energy fluxes is controlled by β-tubulin, bound to VDAC. It is also thought that β-tubulin‒VDAC interaction modulates cellular energy metabolism in cancer, e.g., switching from oxidative phosphorylation to glycolysis. In this review we focus on the described roles of unpolymerized αβ-tubulin heterodimers in regulating VDAC permeability for adenine nucleotides and cellular bioenergetics. We introduce the Mitochondrial Interactosome model and the function of the βII-tubulin subunit in this model in muscle cells and brain synaptosomes, and also consider the role of βIII-tubulin in cancer cells.
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Filipe, Anne, Alexander Chernorudskiy, Sandrine Arbogast, Ersilia Varone, Rocío-Nur Villar-Quiles, Diego Pozzer, Maryline Moulin, et al. "Defective endoplasmic reticulum-mitochondria contacts and bioenergetics in SEPN1-related myopathy." Cell Death & Differentiation 28, no. 1 (July 13, 2020): 123–38. http://dx.doi.org/10.1038/s41418-020-0587-z.
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AbstractSEPN1-related myopathy (SEPN1-RM) is a muscle disorder due to mutations of the SEPN1 gene, which is characterized by muscle weakness and fatigue leading to scoliosis and life-threatening respiratory failure. Core lesions, focal areas of mitochondria depletion in skeletal muscle fibers, are the most common histopathological lesion. SEPN1-RM underlying mechanisms and the precise role of SEPN1 in muscle remained incompletely understood, hindering the development of biomarkers and therapies for this untreatable disease. To investigate the pathophysiological pathways in SEPN1-RM, we performed metabolic studies, calcium and ATP measurements, super-resolution and electron microscopy on in vivo and in vitro models of SEPN1 deficiency as well as muscle biopsies from SEPN1-RM patients. Mouse models of SEPN1 deficiency showed marked alterations in mitochondrial physiology and energy metabolism, suggesting that SEPN1 controls mitochondrial bioenergetics. Moreover, we found that SEPN1 was enriched at the mitochondria-associated membranes (MAM), and was needed for calcium transients between ER and mitochondria, as well as for the integrity of ER-mitochondria contacts. Consistently, loss of SEPN1 in patients was associated with alterations in body composition which correlated with the severity of muscle weakness, and with impaired ER-mitochondria contacts and low ATP levels. Our results indicate a role of SEPN1 as a novel MAM protein involved in mitochondrial bioenergetics. They also identify a systemic bioenergetic component in SEPN1-RM and establish mitochondria as a novel therapeutic target. This role of SEPN1 contributes to explain the fatigue and core lesions in skeletal muscle as well as the body composition abnormalities identified as part of the SEPN1-RM phenotype. Finally, these results point out to an unrecognized interplay between mitochondrial bioenergetics and ER homeostasis in skeletal muscle. They could therefore pave the way to the identification of biomarkers and therapeutic drugs for SEPN1-RM and for other disorders in which muscle ER-mitochondria cross-talk are impaired.
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Willi, Lubna, Ifat Abramovich, Jonatan Fernandez-Garcia, Bella Agranovich, Margarita Shulman, Helena Milman, Polina Baskin, et al. "Bioenergetic and Metabolic Impairments in Induced Pluripotent Stem Cell-Derived Cardiomyocytes Generated from Duchenne Muscular Dystrophy Patients." International Journal of Molecular Sciences 23, no. 17 (August 29, 2022): 9808. http://dx.doi.org/10.3390/ijms23179808.
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Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene and dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality in DMD patients. We tested the hypothesis that DCM is caused by metabolic impairments by employing induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from four DMD patients; an adult male, an adult female, a 7-year-old (7y) male and a 13-year-old (13y) male, all compared to two healthy volunteers. To test the hypothesis, we measured the bioenergetics, metabolomics, electrophysiology, mitochondrial morphology and mitochondrial activity of CMs, using respirometry, LC–MS, patch clamp, electron microscopy (EM) and confocal microscopy methods. We found that: (1) adult DMD CMs exhibited impaired energy metabolism and abnormal mitochondrial structure and function. (2) The 7y CMs demonstrated arrhythmia-free spontaneous firing along with “healthy-like” metabolic status, normal mitochondrial morphology and activity. In contrast, the 13y CMs were mildly arrhythmogenic and showed adult DMD-like bioenergetics deficiencies. (3) In DMD adult CMs, mitochondrial activities were attenuated by 45–48%, whereas the 7y CM activity was similar to that of healthy CMs. (4) In DMD CMs, but not in 7y CMs, there was a 75% decrease in the mitochondrial ATP production rate compared to healthy iPSC-CMs. In summary, DMD iPSC-CMs exhibit bioenergetic and metabolic impairments that are associated with rhythm disturbances corresponding to the patient’s phenotype, thereby constituting novel targets for alleviating cardiomyopathy in DMD patients.
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Cole, Laura K., Genevieve C. Sparagna, Vernon W. Dolinsky, and Grant M. Hatch. "Altered cardiolipin metabolism is associated with cardiac mitochondrial dysfunction in pulmonary vascular remodeled perinatal rat pups." PLOS ONE 17, no. 2 (February 10, 2022): e0263520. http://dx.doi.org/10.1371/journal.pone.0263520.
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Pulmonary vascular remodeling (PVR) in utero results in the development of heart failure. The alterations that occur in cardiac lipid and mitochondrial bioenergetics during the development of in utero PVR was unknown. In this study, PVR was induced in pups in utero by exposure of pregnant dams to indomethacin and hypoxia and cardiac lipids, echocardiographic function and cardiomyocyte mitochondrial function were subsequently examined. Perinatal rat pups with PVR exhibited elevated left and right cardiac ventricular internal dimensions and reduced ejection fraction and fractional shortening compared to controls. Cardiac myocytes from these pups exhibited increased glycolytic capacity and glycolytic reserve compared to controls. However, respiration with glucose as substrate was unaltered. Fatty acid oxidation and ATP-insensitive respiration were increased in isolated cardiac myocytes from these pups compared to controls indicating a mitochondrial dysfunction. Although abundance of mitochondrial respiratory chain complexes was unaltered, increased trilinoleoyl-lysocardiolipin levels in these pups was observed. A compensatory increase in both cardiolipin and phosphatidylethanolamine content were observed due to increased synthesis of these phospholipids. These data indicate that alterations in cardiac cardiolipin and phospholipid metabolism in PVR rat pups is associated with the mitochondrial bioenergetic and cardiac functional defects observed in their hearts.
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Iacobini, Carla, Martina Vitale, Giuseppe Pugliese, and Stefano Menini. "Normalizing HIF-1α Signaling Improves Cellular Glucose Metabolism and Blocks the Pathological Pathways of Hyperglycemic Damage." Biomedicines 9, no. 9 (September 2, 2021): 1139. http://dx.doi.org/10.3390/biomedicines9091139.
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Intracellular metabolism of excess glucose induces mitochondrial dysfunction and diversion of glycolytic intermediates into branch pathways, leading to cell injury and inflammation. Hyperglycemia-driven overproduction of mitochondrial superoxide was thought to be the initiator of these biochemical changes, but accumulating evidence indicates that mitochondrial superoxide generation is dispensable for diabetic complications development. Here we tested the hypothesis that hypoxia inducible factor (HIF)-1α and related bioenergetic changes (Warburg effect) play an initiating role in glucotoxicity. By using human endothelial cells and macrophages, we demonstrate that high glucose (HG) induces HIF-1α activity and a switch from oxidative metabolism to glycolysis and its principal branches. HIF1-α silencing, the carbonyl-trapping and anti-glycating agent ʟ-carnosine, and the glyoxalase-1 inducer trans-resveratrol reversed HG-induced bioenergetics/biochemical changes and endothelial-monocyte cell inflammation, pointing to methylglyoxal (MGO) as the non-hypoxic stimulus for HIF1-α induction. Consistently, MGO mimicked the effects of HG on HIF-1α induction and was able to induce a switch from oxidative metabolism to glycolysis. Mechanistically, methylglyoxal causes HIF1-α stabilization by inhibiting prolyl 4-hydroxylase domain 2 enzyme activity through post-translational glycation. These findings introduce a paradigm shift in the pathogenesis and prevention of diabetic complications by identifying HIF-1α as essential mediator of glucotoxicity, targetable with carbonyl-trapping agents and glyoxalase-1 inducers.
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Sztark, Francois, Monique Malgat, Philippe Dabadie, and Jean-Pierre Mazat. "Comparison of the Effects of Bupivacaine and Ropivacaine on Heart Cell Mitochondrial Bioenergetics." Anesthesiology 88, no. 5 (May 1, 1998): 1340–49. http://dx.doi.org/10.1097/00000542-199805000-00026.
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Background High lipophilic local anesthetics interfere with mitochondrial energy metabolism. These metabolic effects could in part explain some of the toxic effects of local anesthetics, such as bupivacaine-induced myocardial depression. The aim of this study was to compare the bioenergetic effects of the local anesthetics bupivacaine and ropivacaine. Methods The effects of both local anesthetics on mitochondrial energy metabolism were studied in rat heart isolated mitochondria and in saponin-skinned left ventricle fibers. Oxygen consumption, adenosine triphosphate synthesis, and enzymatic activities of the complexes of the respiratory chain were measured. Results Bupivacaine and ropivacaine acted, in isolated mitochondria, as uncouplers between oxygen consumption and phosphorylation of adenosine diphosphate. Further, an inhibitory effect of mitochondrial respiration was evidenced with both anesthetics during maximal respiration and was assigned to a direct inhibition of complex I of the respiratory chain. Mitochondrial adenosine triphosphate synthesis was decreased by both mechanisms. However, both in isolated mitochondria and in permeabilized heart fibers, ropivacaine was less potent than bupivacaine. Adenosine triphosphate synthesis was completely suppressed at 3 mM (approximately 0.1%) bupivacaine, whereas 3 mM ropivacaine induced only about a 40% inhibition. Conclusions Ropivacaine disturbs mitochondrial energy metabolism less than bupivacaine does. The lower lipid solubility of ropivacaine may be responsible for the lesser dose-dependent effects of this drug on mitochondrial bioenergetics.
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McDowell, Ruth E., Khawla F. Ali, Saloni Lad, Vicente T. San Martin, Rita Bottino, Matthew Walsh, Tyler Stevens, William Wilke, John P. Kirwan, and Betul Hatipoglu. "Bioenergetics of Islet Preparations in a Pilot Clinical Trial of Peri-Transplant Hydroxychloroquine for Autologous Islet Transplantation." Cell Transplantation 30 (January 1, 2021): 096368972110574. http://dx.doi.org/10.1177/09636897211057440.
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The inflammatory response is an obstacle to success in both allogeneic and autologous islet transplantation. In autologous islet transplantation (AIT), however, the recipient is also the donor, permitting pretreatment of donor/recipient for a controlled duration prior to transplantation. We sought to exploit this feature of (AIT) by pretreating donor/recipients with chronic pancreatitis undergoing total pancreatectomy and autologous islet transplantation (TPAIT) to test the hypothesis that peri-transplant treatment with the FDA-approved anti-inflammatory hydroxychloroquine (HCQ) improves graft function. In this randomized placebo-controlled pilot clinical study, patients ( n = 6) were treated with oral HCQ for 30 days prior to and 90 days after TPAIT. In vivo islet function was assessed via Mixed Meal Tolerance Testing before HCQ treatment, 6- and 12-months after surgery. In vitro islet bioenergetics were assessed at the time of transplantation via extracellular flux analysis of islet preparation samples from the clinical trial cohort and six additional patients ( n = 12). Our study shows that HCQ did not alter clinical endpoints, but HCQ-treated patients showed greater spare respiratory capacity (SRC) compared to samples from control patients ( P=0.028). Glycolytic metabolism of islet preparations directly correlated with stimulated C-peptide secretion both before and after TPAIT ( P=0.01, R 2=0.489 and P=0.03, R 2=0.674, respectively), and predicted in vivo islet function better than mitochondrial metabolism of islet preps or islet equivalents infused. Overnight culture of islet preparations altered bioenergetic function, significantly decreasing SRC and maximal respiration ( P<0.001). In conclusion, while HCQ did not alter clinical outcomes, it was associated with significantly increased SRC in islet preparations. Bioenergetic analyses of islet preparations suggests that culture should be avoided and that glycolysis may be a more sensitive indicator of in vivo islet function than current metrics, including islet oxygen consumption and islet equivalents infused.
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Shen, Leyao, Guoli Hu, and Courtney M. Karner. "Bioenergetic Metabolism In Osteoblast Differentiation." Current Osteoporosis Reports 20, no. 1 (February 2022): 53–64. http://dx.doi.org/10.1007/s11914-022-00721-2.
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Sreekumar, Parameswaran G., Deborah A. Ferrington, and Ram Kannan. "Glutathione Metabolism and the Novel Role of Mitochondrial GSH in Retinal Degeneration." Antioxidants 10, no. 5 (April 24, 2021): 661. http://dx.doi.org/10.3390/antiox10050661.
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Glutathione (GSH) is present ubiquitously, and its role as a crucial cellular antioxidant in tissues, including the retina, is well established. GSH’s antioxidant function arises from its ability to scavenge reactive oxygen species or to serve as an essential cofactor for GSH S-transferases and peroxidases. This review summarizes the general functions, retinal distribution, disorders linked to GSH deficiency, and the emerging role for mitochondrial GSH (mGSH) in retinal function. Though synthesized only in the cytosol, the presence of GSH in multiple cell organelles suggests the requirement for its active transport across organellar membranes. The localization and distribution of 2-oxoglutarate carrier (OGC) and dicarboxylate carrier (DIC), two recently characterized mitochondrial carrier proteins in RPE and retina, show that these transporters are highly expressed in human retinal pigment epithelium (RPE) cells and retinal layers, and their expression increases with RPE polarity in cultured cells. Depletion of mGSH levels via inhibition of the two transporters resulted in reduced mitochondrial bioenergetic parameters (basal respiration, ATP production, maximal respiration, and spare respiratory capacity) and increased RPE cell death. These results begin to reveal a critical role for mGSH in maintaining RPE bioenergetics and cell health. Thus, augmentation of mGSH pool under GSH-deficient conditions may be a valuable tool in treating retinal disorders, such as age-related macular degeneration and optic neuropathies, whose pathologies have been associated with mitochondrial dysfunction.
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Hubbard, William Brad, Meenakshi Banerjee, Hemendra Vekaria, Kanakanagavalli Shravani Prakhya, Smita Joshi, Qing Jun Wang, Kathryn E. Saatman, Sidney W. Whiteheart, and Patrick G. Sullivan. "Differential Leukocyte and Platelet Profiles in Distinct Models of Traumatic Brain Injury." Cells 10, no. 3 (February 26, 2021): 500. http://dx.doi.org/10.3390/cells10030500.
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Traumatic brain injury (TBI) affects over 3 million individuals every year in the U.S. There is growing appreciation that TBI can produce systemic modifications, which are in part propagated through blood–brain barrier (BBB) dysfunction and blood–brain cell interactions. As such, platelets and leukocytes contribute to mechanisms of thromboinflammation after TBI. While these mechanisms have been investigated in experimental models of contusion brain injury, less is known regarding acute alterations following mild closed head injury. To investigate the role of platelet dynamics and bioenergetics after TBI, we employed two distinct, well-established models of TBI in mice: the controlled cortical impact (CCI) model of contusion brain injury and the closed head injury (CHI) model of mild diffuse brain injury. Hematology parameters, platelet-neutrophil aggregation, and platelet respirometry were assessed acutely after injury. CCI resulted in an early drop in blood leukocyte counts, while CHI increased blood leukocyte counts early after injury. Platelet-neutrophil aggregation was altered acutely after CCI compared to sham. Furthermore, platelet bioenergetic coupling efficiency was transiently reduced at 6 h and increased at 24 h post-CCI. After CHI, oxidative phosphorylation in intact platelets was reduced at 6 h and increased at 24 h compared to sham. Taken together, these data demonstrate that brain trauma initiates alterations in platelet-leukocyte dynamics and platelet metabolism, which may be time- and injury-dependent, providing evidence that platelets carry a peripheral signature of brain injury. The unique trend of platelet bioenergetics after two distinct types of TBI suggests the potential for utilization in prognosis.
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Wright, JaLessa N., Gloria A. Benavides, Michelle S. Johnson, Willayat Wani, Xiaosen Ouyang, Luyun Zou, Helen E. Collins, Jianhua Zhang, Victor Darley-Usmar, and John C. Chatham. "Acute increases in O-GlcNAc indirectly impair mitochondrial bioenergetics through dysregulation of LonP1-mediated mitochondrial protein complex turnover." American Journal of Physiology-Cell Physiology 316, no. 6 (June 1, 2019): C862—C875. http://dx.doi.org/10.1152/ajpcell.00491.2018.
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The attachment of O-linked β- N-acetylglucosamine ( O-GlcNAc) to the serine and threonine residues of proteins in distinct cellular compartments is increasingly recognized as an important mechanism regulating cellular function. Importantly, the O-GlcNAc modification of mitochondrial proteins has been identified as a potential mechanism to modulate metabolism under stress with both potentially beneficial and detrimental effects. This suggests that temporal and dose-dependent changes in O-GlcNAcylation may have different effects on mitochondrial function. In the current study, we found that acutely augmenting O-GlcNAc levels by inhibiting O-GlcNAcase with Thiamet-G for up to 6 h resulted in a time-dependent decrease in cellular bioenergetics and decreased mitochondrial complex I, II, and IV activities. Under these conditions, mitochondrial number was unchanged, whereas an increase in the protein levels of the subunits of several electron transport complex proteins was observed. However, the observed bioenergetic changes appeared not to be due to direct increased O-GlcNAc modification of complex subunit proteins. Increases in O-GlcNAc were also associated with an accumulation of mitochondrial ubiquitinated proteins; phosphatase and tensin homolog induced kinase 1 (PINK1) and p62 protein levels were also significantly increased. Interestingly, the increase in O-GlcNAc levels was associated with a decrease in the protein levels of the mitochondrial Lon protease homolog 1 (LonP1), which is known to target complex IV subunits and PINK1, in addition to other mitochondrial proteins. These data suggest that impaired bioenergetics associated with short-term increases in O-GlcNAc levels could be due to impaired, LonP1-dependent, mitochondrial complex protein turnover.
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Heiden, Matthew Vander. "Cellular Bioenergetics in Lymphoid Neoplasia." Blood 118, no. 21 (November 18, 2011): SCI—25—SCI—25. http://dx.doi.org/10.1182/blood.v118.21.sci-25.sci-25.
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Abstract Abstract SCI-25 Many cancer cells metabolize glucose by aerobic glycolysis, a phenomenon characterized by increased glycolysis with lactate production and decreased oxidative phosphorylation. We have argued that alterations in cell metabolism associated with cancer may be selected by cancer cells to meet the distinct metabolic needs of proliferation. Unlike metabolism in differentiated cells, which is geared toward efficient ATP generation, the metabolism in cancer cells must be adapted to facilitate the accumulation of biomass. Cancer cells divert a larger fraction of their nutrient metabolism to pathways other than mitochondrial respiration regardless of oxygen availability. Nevertheless, oxygen levels still influence how nutrients are metabolized. We have found that the source of carbon used in various anabolic processes varies based on oxygen levels. Furthermore, the enzymes used to metabolize nutrients can also differ based on the cellular context. This includes regulation of isocitrate dehydrogenase, an enzyme that is mutated in some cancers. There is also strong selection for use of the M2 isoform of pyruvate kinase (PK-M2) to metabolize glucose in cancer cell lines. However, evidence from mouse models suggests that PK-M2 is dispensable for glucose metabolism by many tumors in vivo, suggesting an alternate pathway to convert phosphoenolpyruvate to pyruvate can be used to metabolize glucose. This regulation of pyruvate kinase also plays an important role in hematopoietic stem cell biology. Together, these findings argue that distinct metabolic phenotypes exist among proliferating cells, and both environmental and genetic factors influence how metabolism is regulated to support cell growth. Disclosures: Vander Heiden: Agios Pharmaceuticals: Consultancy, Equity Ownership.
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Hafstad, Arild. "The Mysterious Life Energy." Clinical Journal of the International Institute for Bioenergetic Analysis 28, no. 1 (February 2018): 27–43. http://dx.doi.org/10.30820/0743-4804-2018-28-27.
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The paper explores empirical validation of the bioenergetic concept by randomized controlled research on the orgone box. To improve concept validity the author anchors the bioenergetic concept in physical principles and metabolism, combined with principles from Bioenergetic Analysis. The research lends support to the bioenergetic concept by showing that «contextual” stimulation (in the orgone box) can increase free energy in the human organism, indicating influence on a human bioenergetic system. These studies show that the human bioenergetic system is under contextual influence. The orgone theory has formal weaknesses and a sound scientific strategy gives priority to examining the equipment first.
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Bird, Lina J., Violaine Bonnefoy, and Dianne K. Newman. "Bioenergetic challenges of microbial iron metabolisms." Trends in Microbiology 19, no. 7 (July 2011): 330–40. http://dx.doi.org/10.1016/j.tim.2011.05.001.
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Soliman, Ghada, and Ye He. "Mitochondrial Bioenergetics Profile With Different Mechanistic Target of Rapamycin Complexes (mTORC1/mTORC2) Inhibitors in Pancreatic Beta-Cell Lines (Beta-TC-6)." Current Developments in Nutrition 5, Supplement_2 (June 2021): 528. http://dx.doi.org/10.1093/cdn/nzab041_043.
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Abstract Objectives We investigated the impact of mTOR complexes inhibition with RapaLink-1, a third-generation bivalent mTORC1/mTORC2 inhibitor that links rapamycin with a mTOR-kinase inhibitor, or Torin-2 (ATP-competitive) on mitochondrial dynamics, bioenergetics, and extracellular flux. Methods We used insulin-secreting, glucose-responsive pancreatic beta cells derived from transgenic mice expressing SV40 (Beta-TC-6 cells, ATCC-11506). Cells were treated for 24 hours with either: RapaLink; Torin-2; rapamycin; metformin; a combination of metformin and RapaLink, or Torin-2; compared to vehicle control. Bioenergetic dynamics and cellular metabolism were quantified using MitoStress Test XF24 (Agilent, Seahorse). The real-time, live-cell approach simultaneously measures oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) to determine cellular respiration and metabolism. Statistical significance was assessed by ANOVA followed by an unpaired t-test. Results Rapalink-1 and Torin-2 incubation decreased basal OCR compared to rapamycin alone or vehicle control (189.58 ± 48.58, 116.85 ± 26.55 versus 405.01 ± 21.57, 444.19 ± 58.59, p < 0.01) in Beta TC-6 pancreatic cell lines. ATP production was also significantly reduced in RapaLink-1 (122.23 ± 33.19), Torin-2 (72.37 ± 17.33) treated cells, compared to rapamycin (250.45 ± 9.41) and vehicle control (274.23 ± 38.17), p < 0.01. Similarly, proton leak decreased in RapaLink-1 (67.34 ± 15.40) and Torin-2 (44.48 ± 9.23) treated beta cells, compared to rapamycin (154.56 ± 12.53) or control (169.96 ± 20.52), p < 0.01. However, non-mitochondrial oxygen consumption was not statistically different between RapaLink (67.17 ± 3.52) Torin-2 (55.93 ± 8.76) or rapamycin (80.01 ± 4.36), but was less than the control group (108.80 ± 7.19), p = 0.006. Conclusions The combination of mTORC1 and mTORC2 inhibition by RapaLink-1 or Torin-2 decreased mitochondrial respiration compared to rapamycin treatment. Decreased OCR suggests reduced initial energy requirements, while decreased ATP production indicates decreased energy demands. Third-generation mTOR inhibitors may alter the mitochondrial dynamics and reveal a mitochondrial bioenergetics profile that could be targeted to reduce mitochondrial stress. Funding Sources City University of New York, GC Advanced Science Research Center Seed Grant Award
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Oliveira, Wellington de Almeida, Renata Emmanuele Assunção Santos, Gizele Santiago de Moura Silva, Kelli Nogueira Ferraz-Pereira, Ana Lisa do Vale Gomes, and Mariana Pinheiro Fernandes. "Mitochondrial bioenergetics and oxidative balance in in vitro arbovirus infection models: a systematic review." Research, Society and Development 11, no. 16 (December 7, 2022): e266111637749. http://dx.doi.org/10.33448/rsd-v11i16.37749.
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Introduction: Viral infections affect oxidative metabolism and may have repercussions on mitochondrial alterations, compromising cellular homeostasis. Objectives: To assess mitochondrial bioenergetics and oxidative balance in in vitro arbovirus infection models. Methods: The review was written in accordance with the PRISMA and submitted to the Open Science FrameWork platform with DOI 10.17605 / OSF.IO / 8ZFSW. Were used the Descriptors/MeSH (Arbovirus, Arboviruses, Arbovirus infections, Mitochondria, Oxidative stress and Reactive oxygen species) was carried out on the platforms: PubMed, SCOPUS, COCHRANE, Lilacs and Web of Science. The quality analysis of the studies was performed using the ARRIVE tool adapted to the CONSORT, followed by the KAPPA concordance test, were used 24 articles. Results: Results show morphological alterations in the mitochondria, such as swelling, fragmentation, and the appearance of membranes. Mitochondrial stretching was more intense in regions close to the convoluted zones, associated with changes in the genes of mitochondrial dynamics. Changes in oxidative stress biomarkers, antioxidant enzymes and ROS production were evident in most articles, except for those that used cells of immunological origin. Conclusion: Changes in mitochondrial bioenergetic can assist the virus in the replication process, however, these changes can result causing damage cell and of oxidative stress.
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Fernández-Acosta, Roberto, Behrouz Hassannia, Jurgen Caroen, Bartosz Wiernicki, Daniel Alvarez-Alminaque, Bruno Verstraeten, Johan Van der Eycken, Peter Vandenabeele, Tom Vanden Berghe, and Gilberto L. Pardo-Andreu. "Molecular Mechanisms of Nemorosone-Induced Ferroptosis in Cancer Cells." Cells 12, no. 5 (February 24, 2023): 735. http://dx.doi.org/10.3390/cells12050735.
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Ferroptosis is an iron-dependent cell death-driven by excessive peroxidation of polyunsaturated fatty acids (PUFAs) of membranes. A growing body of evidence suggests the induction of ferroptosis as a cutting-edge strategy in cancer treatment research. Despite the essential role of mitochondria in cellular metabolism, bioenergetics, and cell death, their function in ferroptosis is still poorly understood. Recently, mitochondria were elucidated as an important component in cysteine-deprivation-induced (CDI) ferroptosis, which provides novel targets in the search for new ferroptosis-inducing compounds (FINs). Here, we identified the natural mitochondrial uncoupler nemorosone as a ferroptosis inducer in cancer cells. Interestingly, nemorosone triggers ferroptosis by a double-edged mechanism. In addition to decreasing the glutathione (GSH) levels by blocking the System xc cystine/glutamate antiporter (SLC7A11), nemorosone increases the intracellular labile Fe2+ pool via heme oxygenase-1 (HMOX1) induction. Interestingly, a structural variant of nemorosone (O-methylated nemorosone), having lost the capacity to uncouple mitochondrial respiration, does not trigger cell death anymore, suggesting that the mitochondrial bioenergetic disruption via mitochondrial uncoupling is necessary for nemorosone-induced ferroptosis. Our results open novel opportunities for cancer cell killing by mitochondrial uncoupling-induced ferroptosis.
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Xu, Weiling, Allison J. Janocha, and Serpil C. Erzurum. "Metabolism in Pulmonary Hypertension." Annual Review of Physiology 83, no. 1 (February 10, 2021): 551–76. http://dx.doi.org/10.1146/annurev-physiol-031620-123956.
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Pulmonary arterial hypertension (PAH) is characterized by impaired regulation of pulmonary hemodynamics and vascular growth. Alterations of metabolism and bioenergetics are increasingly recognized as universal hallmarks of PAH, as metabolic abnormalities are identified in lungs and hearts of patients, animal models of the disease, and cells derived from lungs of patients. Mitochondria are the primary organelle critically mediating the complex and integrative metabolic pathways in bioenergetics, biosynthetic pathways, and cell signaling. Here, we review the alterations in metabolic pathways that are linked to the pathologic vascular phenotype of PAH, including abnormalities in glycolysis and glucose oxidation, fatty acid oxidation, glutaminolysis, arginine metabolism, one-carbon metabolism, the reducing and oxidizing cell environment, and the tricarboxylic acid cycle, as well as the effects of PAH-associated nuclear and mitochondrial mutations on metabolism. Understanding of the metabolic mechanisms underlying PAH provides important knowledge for the design of new therapeutics for treatment of patients.
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Mohamad Hazir, Nur Shukriyah, Nor Hamdan Mohamad Yahaya, Muhamad Syahrul Fitri Zawawi, Hanafi Ahmad Damanhuri, Norazlina Mohamed, and Ekram Alias. "Changes in Metabolism and Mitochondrial Bioenergetics during Polyethylene-Induced Osteoclastogenesis." International Journal of Molecular Sciences 23, no. 15 (July 28, 2022): 8331. http://dx.doi.org/10.3390/ijms23158331.
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Changes in mitochondrial bioenergetics are believed to take place during osteoclastogenesis. This study aims to assess changes in mitochondrial bioenergetics and reactive oxygen species (ROS) levels during polyethylene (PE)-induced osteoclastogenesis in vitro. For this purpose, RAW264.7 cells were cultured for nine days and allowed to differentiate into osteoclasts in the presence of PE and RANKL. The total TRAP-positive cells, resorption activity, expression of osteoclast marker genes, ROS level, mitochondrial bioenergetics, glycolysis, and substrate utilization were measured. The effect of tocotrienols-rich fraction (TRF) treatment (50 ng/mL) on those parameters during PE-induced osteoclastogenesis was also studied. During PE-induced osteoclastogenesis, as depicted by an increase in TRAP-positive cells and gene expression of osteoclast-related markers, higher proton leak, higher extracellular acidification rate (ECAR), as well as higher levels of ROS and NADPH oxidases (NOXs) were observed in the differentiated cells. The oxidation level of some substrates in the differentiated group was higher than in other groups. TRF treatment significantly reduced the number of TRAP-positive osteoclasts, bone resorption activity, and ROS levels, as well as modulating the gene expression of antioxidant-related genes and mitochondrial function. In conclusion, changes in mitochondrial bioenergetics and substrate utilization were observed during PE-induced osteoclastogenesis, while TRF treatment modulated these changes.