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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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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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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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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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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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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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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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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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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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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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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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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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Nilsson, Thomas, Maria Rova, and Anna Smedja Bäcklund. "Microbial metabolism of oxochlorates: A bioenergetic perspective." Biochimica et Biophysica Acta (BBA) - Bioenergetics 1827, no. 2 (February 2013): 189–97. http://dx.doi.org/10.1016/j.bbabio.2012.06.010.
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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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Oren, Aharon. "Bioenergetic Aspects of Halophilism." Microbiology and Molecular Biology Reviews 63, no. 2 (June 1, 1999): 334–48. http://dx.doi.org/10.1128/mmbr.63.2.334-348.1999.
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SUMMARY Examinination of microbial diversity in environments of increasing salt concentrations indicates that certain types of dissimilatory metabolism do not occur at the highest salinities. Examples are methanogenesis for H2 + CO2 or from acetate, dissimilatory sulfate reduction with oxidation of acetate, and autotrophic nitrification. Occurrence of the different metabolic types is correlated with the free-energy change associated with the dissimilatory reactions. Life at high salt concentrations is energetically expensive. Most bacteria and also the methanogenic archaea produce high intracellular concentrations of organic osmotic solutes at a high energetic cost. All halophilic microorganisms expend large amounts of energy to maintain steep gradients of NA+ and K+ concentrations across their cytoplasmic membrane. The energetic cost of salt adaptation probably dictates what types of metabolism can support life at the highest salt concentrations. Use of KCl as an intracellular solute, while requiring far-reaching adaptations of the intracellular machinery, is energetically more favorable than production of organic-compatible solutes. This may explain why the anaerobic halophilic fermentative bacteria (order Haloanaerobiales) use this strategy and also why halophilic homoacetogenic bacteria that produce acetate from H2 + CO2 exist whereas methanogens that use the same substrates in a reaction with a similar free-energy yield do not.
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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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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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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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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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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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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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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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Cotter, David G., Rebecca C. Schugar, and Peter A. Crawford. "Ketone body metabolism and cardiovascular disease." American Journal of Physiology-Heart and Circulatory Physiology 304, no. 8 (April 15, 2013): H1060—H1076. http://dx.doi.org/10.1152/ajpheart.00646.2012.
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Ketone bodies are metabolized through evolutionarily conserved pathways that support bioenergetic homeostasis, particularly in brain, heart, and skeletal muscle when carbohydrates are in short supply. The metabolism of ketone bodies interfaces with the tricarboxylic acid cycle, β-oxidation of fatty acids, de novo lipogenesis, sterol biosynthesis, glucose metabolism, the mitochondrial electron transport chain, hormonal signaling, intracellular signal transduction pathways, and the microbiome. Here we review the mechanisms through which ketone bodies are metabolized and how their signals are transmitted. We focus on the roles this metabolic pathway may play in cardiovascular disease states, the bioenergetic benefits of myocardial ketone body oxidation, and prospective interactions among ketone body metabolism, obesity, metabolic syndrome, and atherosclerosis. Ketone body metabolism is noninvasively quantifiable in humans and is responsive to nutritional interventions. Therefore, further investigation of this pathway in disease models and in humans may ultimately yield tailored diagnostic strategies and therapies for specific pathological states.
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Roy, Nairita, Meredith May, Evan Ryan Delgado, Frances Alencastro, Patrick David Wilkinson, Mei Smyers, Michael John Reynolds, Sruti Shiva, and Andrew Wayne Duncan. "SLC25A34 regulates bioenergetic metabolism in the murine liver." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.03444.
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Boyd, Eric S., Maximiliano J. Amenabar, Saroj Poudel, and Alexis S. Templeton. "Bioenergetic constraints on the origin of autotrophic metabolism." Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences 378, no. 2165 (January 6, 2020): 20190151. http://dx.doi.org/10.1098/rsta.2019.0151.
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Autotrophs form the base of all complex food webs and seemingly have done so since early in Earth history. Phylogenetic evidence suggests that early autotrophs were anaerobic, used CO 2 as both an oxidant and carbon source, were dependent on H 2 as an electron donor, and used iron-sulfur proteins (termed ferredoxins) as a primary electron carrier. However, the reduction potential of H 2 is not typically low enough to efficiently reduce ferredoxin. Instead, in modern strictly anaerobic and H 2 -dependent autotrophs, ferredoxin reduction is accomplished using one of several recently evolved enzymatic mechanisms, including electron bifurcating and coupled ion translocating mechanisms. These observations raise the intriguing question of why anaerobic autotrophs adopted ferredoxins as central electron carriers only to have to evolve complex machinery to reduce them. Here, we report calculated reduction potentials for H 2 as a function of observed environmental H 2 concentration, pH and temperature. Results suggest that a combination of alkaline pH and high H 2 concentration yield H 2 reduction potentials low enough to efficiently reduce ferredoxins. Hyperalkaline, H 2 rich environments have existed in discrete locations throughout Earth history where ultramafic minerals are undergoing hydration through the process of serpentinization. These results suggest that serpentinizing systems, which would have been common on early Earth, naturally produced conditions conducive to the emergence of H 2 -dependent autotrophic life. The primitive process of hydrogenotrophic methanogenesis is used to examine potential changes in methanogenesis and Fd reduction pathways as these organisms diversified away from serpentinizing environments. This article is part of a discussion meeting issue ‘Serpentinite in the earth system’.
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Germain, Marc. "OPA1 and mitochondrial solute carriers in bioenergetic metabolism." Molecular & Cellular Oncology 2, no. 2 (January 7, 2015): e982378. http://dx.doi.org/10.4161/23723556.2014.982378.
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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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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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Nagy, Csörsz, and Arvand Haschemi. "Sedoheptulose kinase regulates cellular carbohydrate metabolism by sedoheptulose 7-phosphate supply." Biochemical Society Transactions 41, no. 2 (March 21, 2013): 674–80. http://dx.doi.org/10.1042/bst20120354.
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Dynamic carbon re-routing between catabolic and anabolic metabolism is an essential element of cellular transformation associated with tumour formation and immune cell activation. Such bioenergetic adaptations are important for cellular function and therefore require tight control. Carbohydrate phosphorylation has been proposed as a rate-limiting step of several metabolic networks. The recent identification of a sedoheptulose kinase indicated that free sedoheptulose is a relevant and accessible carbon source in humans. Furthermore, the bioavailability of its phosphorylated form, sedoheptulose 7-phosphate, appears to function as a rheostat for carbon-flux at the interface of glycolysis and the pentose phosphate pathway. In the present paper, we review reports of sedoheptulose metabolism, compare it with glucose metabolism, and discuss the regulation of sedoheptulose kinase as mechanism to achieve bioenergetic reprogramming in cells.
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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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Sousa, Filipa L., Thorsten Thiergart, Giddy Landan, Shijulal Nelson-Sathi, Inês A. C. Pereira, John F. Allen, Nick Lane, and William F. Martin. "Early bioenergetic evolution." Philosophical Transactions of the Royal Society B: Biological Sciences 368, no. 1622 (July 19, 2013): 20130088. http://dx.doi.org/10.1098/rstb.2013.0088.
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Life is the harnessing of chemical energy in such a way that the energy-harnessing device makes a copy of itself. This paper outlines an energetically feasible path from a particular inorganic setting for the origin of life to the first free-living cells. The sources of energy available to early organic synthesis, early evolving systems and early cells stand in the foreground, as do the possible mechanisms of their conversion into harnessable chemical energy for synthetic reactions. With regard to the possible temporal sequence of events, we focus on: (i) alkaline hydrothermal vents as the far-from-equilibrium setting, (ii) the Wood–Ljungdahl (acetyl-CoA) pathway as the route that could have underpinned carbon assimilation for these processes, (iii) biochemical divergence, within the naturally formed inorganic compartments at a hydrothermal mound, of geochemically confined replicating entities with a complexity below that of free-living prokaryotes, and (iv) acetogenesis and methanogenesis as the ancestral forms of carbon and energy metabolism in the first free-living ancestors of the eubacteria and archaebacteria, respectively. In terms of the main evolutionary transitions in early bioenergetic evolution, we focus on: (i) thioester-dependent substrate-level phosphorylations, (ii) harnessing of naturally existing proton gradients at the vent–ocean interface via the ATP synthase, (iii) harnessing of Na + gradients generated by H + /Na + antiporters, (iv) flavin-based bifurcation-dependent gradient generation, and finally (v) quinone-based (and Q-cycle-dependent) proton gradient generation. Of those five transitions, the first four are posited to have taken place at the vent. Ultimately, all of these bioenergetic processes depend, even today, upon CO 2 reduction with low-potential ferredoxin (Fd), generated either chemosynthetically or photosynthetically, suggesting a reaction of the type ‘reduced iron → reduced carbon’ at the beginning of bioenergetic evolution.
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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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DeBerardinis, Ralph J., and Navdeep S. Chandel. "Fundamentals of cancer metabolism." Science Advances 2, no. 5 (May 2016): e1600200. http://dx.doi.org/10.1126/sciadv.1600200.
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Tumors reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells. These reprogrammed activities are now recognized as hallmarks of cancer, and recent work has uncovered remarkable flexibility in the specific pathways activated by tumor cells to support these key functions. In this perspective, we provide a conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis. Understanding these concepts will progressively support the development of new strategies to treat human cancer.
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Kanbe, Katsuaki, Atsushi Hasegawa, Kenji Takagishi, Kenji Shirakura, Mitsuo Nagase, Takashi Yanagawa, and Katsumi Tomiyoshi. "Analysis of Muscle Bioenergetic Metabolism in Rabbit Leg Lengthening." Clinical Orthopaedics and Related Research 351 (June 1998): 214???221. http://dx.doi.org/10.1097/00003086-199806000-00026.
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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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Cioffi, Federica, Antonia Giacco, Fernando Goglia, and Elena Silvestri. "Bioenergetic Aspects of Mitochondrial Actions of Thyroid Hormones." Cells 11, no. 6 (March 15, 2022): 997. http://dx.doi.org/10.3390/cells11060997.
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Much is known, but there is also much more to discover, about the actions that thyroid hormones (TH) exert on metabolism. Indeed, despite the fact that thyroid hormones are recognized as one of the most important regulators of metabolic rate, much remains to be clarified on which mechanisms control/regulate these actions. Given their actions on energy metabolism and that mitochondria are the main cellular site where metabolic transformations take place, these organelles have been the subject of extensive investigations. In relatively recent times, new knowledge concerning both thyroid hormones (such as the mechanisms of action, the existence of metabolically active TH derivatives) and the mechanisms of energy transduction such as (among others) dynamics, respiratory chain organization in supercomplexes and cristes organization, have opened new pathways of investigation in the field of the control of energy metabolism and of the mechanisms of action of TH at cellular level. In this review, we highlight the knowledge and approaches about the complex relationship between TH, including some of their derivatives, and the mitochondrial respiratory chain.
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Nicholls, David G. "The Pancreatic β-Cell: A Bioenergetic Perspective." Physiological Reviews 96, no. 4 (October 2016): 1385–447. http://dx.doi.org/10.1152/physrev.00009.2016.
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The pancreatic β-cell secretes insulin in response to elevated plasma glucose. This review applies an external bioenergetic critique to the central processes of glucose-stimulated insulin secretion, including glycolytic and mitochondrial metabolism, the cytosolic adenine nucleotide pool, and its interaction with plasma membrane ion channels. The control mechanisms responsible for the unique responsiveness of the cell to glucose availability are discussed from bioenergetic and metabolic control standpoints. The concept of coupling factor facilitation of secretion is critiqued, and an attempt is made to unravel the bioenergetic basis of the oscillatory mechanisms controlling secretion. The need to consider the physiological constraints operating in the intact cell is emphasized throughout. The aim is to provide a coherent pathway through an extensive, complex, and sometimes bewildering literature, particularly for those unfamiliar with the field.
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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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Tung, Stephanie, Yonghong Shi, Karry Wong, Fang Zhu, Reg Gorczynski, Robert C. Laister, Mark Minden, et al. "PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia." Blood 122, no. 6 (August 8, 2013): 969–80. http://dx.doi.org/10.1182/blood-2013-03-489468.
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Key Points Glucocorticoids downregulate PKM2 and metabolism in CLL cells, impairing access to bioenergetic programs needed to repair cell damage. PPARα and fatty acid oxidation antagonists potentiate the cytotoxic effects of glucocorticoids.
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Liu, Lingling, Yun Lu, Jennifer Martinez, Yujing Bi, Gaojian Lian, Tingting Wang, Sandra Milasta, et al. "Proinflammatory signal suppresses proliferation and shifts macrophage metabolism from Myc-dependent to HIF1α-dependent." Proceedings of the National Academy of Sciences 113, no. 6 (January 25, 2016): 1564–69. http://dx.doi.org/10.1073/pnas.1518000113.
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As a phenotypically plastic cellular population, macrophages change their physiology in response to environmental signals. Emerging evidence suggests that macrophages are capable of tightly coordinating their metabolic programs to adjust their immunological and bioenergetic functional properties, as needed. Upon mitogenic stimulation, quiescent macrophages enter the cell cycle, increasing their bioenergetic and biosynthetic activity to meet the demands of cell growth. Proinflammatory stimulation, however, suppresses cell proliferation, while maintaining a heightened metabolic activity imposed by the production of bactericidal factors. Here, we report that the mitogenic stimulus, colony-stimulating factor 1 (CSF-1), engages a myelocytomatosis viral oncogen (Myc)-dependent transcriptional program that is responsible for cell cycle entry and the up-regulation of glucose and glutamine catabolism in bone marrow-derived macrophages (BMDMs). However, the proinflammatory stimulus, lipopolysaccharide (LPS), suppresses Myc expression and cell proliferation and engages a hypoxia-inducible factor alpha (HIF1α)-dependent transcriptional program that is responsible for heightened glycolysis. The acute deletion of Myc or HIF1α selectively impaired the CSF-1– or LPS-driven metabolic activities in BMDM, respectively. Finally, inhibition of glycolysis by 2-deoxyglucose (2-DG) or genetic deletion of HIF1α suppressed LPS-induced inflammation in vivo. Our studies indicate that a switch from a Myc-dependent to a HIF1α-dependent transcriptional program may regulate the robust bioenergetic support for an inflammatory response, while sparing Myc-dependent proliferation.
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Readnower, Ryan D., Robert E. Brainard, Bradford G. Hill, and Steven P. Jones. "Standardized bioenergetic profiling of adult mouse cardiomyocytes." Physiological Genomics 44, no. 24 (December 15, 2012): 1208–13. http://dx.doi.org/10.1152/physiolgenomics.00129.2012.
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Mitochondria are at the crux of life and death and as such have become ideal targets of intervention in cardiovascular disease. Generally, current methods to measure mitochondrial dysfunction rely on working with the isolated organelle and fail to incorporate mitochondrial function in a cellular context. Extracellular flux methodology has been particularly advantageous in this respect; however, certain primary cell types, such as adult cardiac myocytes, have been difficult to standardize with this technology. Here, we describe methods for using extracellular flux (XF) analysis to measure mitochondrial bioenergetics in isolated, intact, adult mouse cardiomyocytes (ACMs). Following isolation, ACMs were seeded overnight onto laminin-coated (20 μg/ml) microplates, which resulted in high attachment efficiency. After establishing seeding density, we found that a commonly used assay medium (containing a supraphysiological concentration of pyruvate at 1 mmol/l) produced a maximal bioenergetic response. After performing a pyruvate dose-response, we determined that pyruvate titrated to 0.1 mmol/l was optimal for examining alternative substrate oxidation. Methods for measuring fatty acid oxidation were established. These methods lay the framework using XF analysis to profile metabolism of ACMs and will likely augment our ability to understand mitochondrial dysfunction in heart failure and acute myocardial ischemia. This platform could easily be extended to models of diabetes or other metabolic defects.
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Li, Zongdong, Natasha M. Nesbitt, Lisa E. Malone, Dimitri V. Gnatenko, Song Wu, Daifeng Wang, Wei Zhu, Geoffrey D. Girnun, and Wadie F. Bahou. "Heme degradation enzyme biliverdin IXβ reductase is required for stem cell glutamine metabolism." Biochemical Journal 475, no. 6 (March 29, 2018): 1211–23. http://dx.doi.org/10.1042/bcj20180016.
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Bioenergetic requirements of hematopoietic stem cells and pluripotent stem cells (PSCs) vary with lineage fate, and cellular adaptations rely largely on substrate (glucose/glutamine) availability and mitochondrial function to balance tricarboxylic acid (TCA)-derived anabolic and redox-regulated antioxidant functions. Heme synthesis and degradation converge in a linear pathway that utilizes TCA cycle-derived carbon in cataplerotic reactions of tetrapyrrole biosynthesis, terminated by NAD(P)H-dependent biliverdin reductases (IXα, BLVRA and IXβ, BLVRB) that lead to bilirubin generation and cellular antioxidant functions. We now demonstrate that PSCs with targeted deletion of BLVRB display physiologically defective antioxidant activity and cellular viability, associated with a glutamine-restricted defect in TCA entry that was computationally predicted using gene/metabolite topological network analysis and subsequently validated by bioenergetic and isotopomeric studies. Defective BLVRB-regulated glutamine utilization was accompanied by exaggerated glycolytic accumulation of the rate-limiting hexokinase reaction product glucose-6-phosphate. BLVRB-deficient embryoid body formation (a critical size parameter of early lineage fate potential) demonstrated enhanced sensitivity to the pentose phosphate pathway (PPP) inhibitor 6-aminonicotinamide with no differences in the glycolytic pathway inhibitor 2-deoxyglucose. These collective data place heme catabolism in a crucial pathway of glutamine-regulated bioenergetic metabolism and suggest that early stages of lineage fate potential require glutamine anaplerotic functions and an intact PPP, which are, in part, regulated by BLVRB activity. In principle, BLVRB inhibition represents an alternative strategy for modulating cellular glutamine utilization with consequences for cancer and hematopoietic metabolism.
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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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Klimova, Nina, and Tibor Kristian. "Multi-targeted Effect of Nicotinamide Mononucleotide on Brain Bioenergetic Metabolism." Neurochemical Research 44, no. 10 (January 19, 2019): 2280–87. http://dx.doi.org/10.1007/s11064-019-02729-0.
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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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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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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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Paterson, Gordon, Susan Y. Huestis, D. Michael Whittle, Kenneth G. Drouillard, and G. Douglas Haffner. "In situ measurement of tissue turnover and energy conversion efficiencies in lake trout (Salvelinus namaycush) using a novel toxicokinetic approach." Canadian Journal of Fisheries and Aquatic Sciences 62, no. 2 (February 1, 2005): 464–71. http://dx.doi.org/10.1139/f04-206.
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We determined polychlorinated biphenyl (PCB) elimination patterns in lake trout (Salvelinus namaycush) from Lake Ontario using biomonitoring data collected from 1977 to 1993. The in situ elimination rates of these persistent pollutants were found to describe tissue turnover rates in lake trout. A model relating tissue turnover rates and endogenous energy conversion efficiencies revealed that chemical elimination in larger organisms is primarily regulated by food limitation and bioenergetic mechanisms rather than chemical kinetics. Lake trout approximately 2500 g and larger were observed to have higher PCB elimination rates than smaller fish as a result of increased lipid mobilization to supplement metabolic demands due to increased time spent foraging. This study concludes that the growth and production of large predators in Lake Ontario are regulated by the bioenergetic constraints of searching for prey in a food-limited environment. We also demonstrate that persistent organic pollutant kinetics can describe the proportion of endogenous energy required to support metabolism and production, thus providing important in situ measurements of bioenergetic processes.