bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2024–12–22
24 papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello
  1. Exogenous Ketones in Cardiovascular Disease and Diabetes: From Bench to Bedside.
  2. The Cardioprotective Effects of Nutritional Ketosis: Mechanisms and Clinical Implications.
  3. Can Endogenous or Exogenous Ketosis Tackle the Constraints of Ultra-Endurance Exercise?
  4. Does the Ketogenic Diet Mediate Inflammation Markers in Obese and Overweight Adults? A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
  5. Effects of a 12 Week Ketogenic Diet Intervention on Obese and Overweight Females with Glucose and Lipid Metabolism Disturbance.
  6. SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts.
  7. A bile acid could explain how calorie restriction slows ageing.
  8. Beyond ketosis: the search for the mechanism underlying SGLT2-inhibitor benefit continues.
  9. Mapping mitochondrial aging.
  10. 1,3-butanediol administration as an alternative strategy to calorie restriction for neuroprotection - Insights into modulation of stress response in hippocampus of healthy rats.
  11. Role of Fatty Acids β-Oxidation in the Metabolic Interactions Between Organs.
  12. Unraveling the priming phase of NLRP3 inflammasome activation: Molecular insights and clinical relevance.
  13. Exercise as Mitochondrial Medicine: How Does the Exercise Prescription Affect Mitochondrial Adaptations to Training?
  14. Effects of contraction frequency during high-intensity training on fatigue resistance and aerobic adaptations in mouse skeletal muscle.
  15. Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.
  16. Time-of-day control of mitochondria regulates NLRP3 inflammasome activation in macrophages.
  17. Acute treadmill exercise induces mitochondrial unfolded protein response in skeletal muscle of male rats.
  18. NAD+ Boosting Strategies.
  19. Too old for healthy aging? Exploring age limits of longevity treatments.
  20. Sarcopenic obesity is attenuated by E-syt1 inhibition via improving skeletal muscle mitochondrial function.
  21. Inter- and intracellular mitochondrial communication: signaling hubs in aging and age-related diseases.
  22. Fantastic proteins and where to find them - histones, in the nucleus and beyond.
  23. Impact of exercise and fasting on mitochondrial regulators in human muscle.
  24. FKBP5 as a key regulator of metabolic processes in birds: Insights from chicken pectoral muscle.
  1. J Clin Med. 2024 Dec 04. pii: 7391. [Epub ahead of print]13(23):
    Exogenous Ketones in Cardiovascular Disease and Diabetes: From Bench to Bedside.
    Urna Kansakar, Crystal Nieves Garcia, Gaetano Santulli, Jessica Gambardella, Pasquale Mone, Stanislovas S Jankauskas, Angela Lombardi.
      Ketone bodies are molecules produced from fatty acids in the liver that act as energy carriers to peripheral tissues when glucose levels are low. Carbohydrate- and calorie-restricted diets, known to increase the levels of circulating ketone bodies, have attracted significant attention in recent years due to their potential health benefits in several diseases. Specifically, increasing ketones through dietary modulation has been reported to be beneficial for cardiovascular health and to improve glucose homeostasis and insulin resistance. Interestingly, although excessive production of ketones may lead to life-threatening ketoacidosis in diabetic patients, mounting evidence suggests that modest levels of ketones play adaptive and beneficial roles in pancreatic beta cells, although the exact mechanisms are still unknown. Of note, Sodium-Glucose Transporter 2 (SGLT2) inhibitors have been shown to increase the levels of beta-hydroxybutyrate (BHB), the most abundant ketone circulating in the human body, which may play a pivotal role in mediating some of their protective effects in cardiovascular health and diabetes. This systematic review provides a comprehensive overview of the scientific literature and presents an analysis of the effects of ketone bodies on cardiovascular pathophysiology and pancreatic beta cell function. The evidence from both preclinical and clinical studies indicates that exogenous ketones may have significant beneficial effects on both cardiomyocytes and pancreatic beta cells, making them intriguing candidates for potential cardioprotective therapies and to preserve beta cell function in patients with diabetes.
    Keywords:  BHB; SGLT2 inhibitors; cardiovascular disease; diabetes; exogenous ketones; metabolism; supplements
    DOI:  https://doi.org/10.3390/jcm13237391
  2. Nutrients. 2024 Dec 05. pii: 4204. [Epub ahead of print]16(23):
    The Cardioprotective Effects of Nutritional Ketosis: Mechanisms and Clinical Implications.
    Claudia Venturini, Lucia Mancinelli, Giulia Matacchione, Fabiola Olivieri, Roberto Antonicelli.
      Cardiovascular diseases (CVDs) persist as the primary cause of death worldwide, accounting for roughly 17.9 million fatalities each year. The prevalence of obesity, metabolic syndrome, and type 2 diabetes (key risk factors for CVD) continues to escalate at an alarming rate, necessitating novel therapeutic strategies to address this global health crisis. Nutritional ketosis, induced through ketogenic diets, modified fasting, intermittent fasting, and medium-chain triglyceride (MCT) oil consumption, has garnered attention for its potential cardioprotective effects. Ketosis is a metabolic state in which the body, due to a significantly reduced intake of carbohydrates, shifts its primary energy source from glucose to ketone bodies, i.e., beta-hydroxybutyrate (BHB), acetoacetate, and acetone, which are produced in the liver from fatty acids. This review examines the mechanisms by which ketone bodies, particularly BHB, mitigate cardiovascular risk. We focus mainly on the anti-inflammatory and antioxidative properties of BHB and summarize recent evidence to highlight the clinical relevance of ketosis in cardiometabolic health.
    Keywords:  beta-hydroxybutyrate; cardiovascular risk; inflammation; ketogenic diet; obesity
    DOI:  https://doi.org/10.3390/nu16234204
  3. Exerc Sport Sci Rev. 2024 Dec 16.
    Can Endogenous or Exogenous Ketosis Tackle the Constraints of Ultra-Endurance Exercise?
    Louise Engelbrecht, Elmarie Terblanche, Katrien Koppo, Chiel Poffé.
       ABSTRACT: A high-fat, low-carbohydrate, ketogenic diet has already appealed to athletes for a long time due to its purported ability to improve exercise performance and post-exercise recovery. The availability of ketone supplements has further sparked such interest. The review therefore focuses on the potential beneficial impact of exogenous and endogenous ketosis in the context of ultra-endurance exercise.
    DOI:  https://doi.org/10.1249/JES.0000000000000357
  4. Nutrients. 2024 Nov 22. pii: 4002. [Epub ahead of print]16(23):
    Does the Ketogenic Diet Mediate Inflammation Markers in Obese and Overweight Adults? A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
    Mariangela Rondanelli, Clara Gasparri, Martina Pirola, Gaetan Claude Barrile, Alessia Moroni, Ignacio Sajoux, Simone Perna.
      Background/Objectives. The ketogenic diet has emerged as a potential treatment strategy for reducing inflammation. The purpose of this meta-analysis and systematic review is to look into how a ketogenic diet affects inflammatory biomarkers in persons who are overweight or obese. Methods. We conducted an extensive search of Web of Science, PubMed, Scopus, and Google Scholar to find pertinent studies reporting changes in inflammatory biomarkers such as C-reactive protein (CRP), the erythrocyte sedimentation rate, and cytokines after a ketogenic diet. Results. Seven randomized controlled trials involving 218 overweight or obese individuals who followed a ketogenic or control diet over 8 weeks to 2 years were included in the review, and five of those were considered for the meta-analysis. The primary outcomes were CRP and IL-6 levels. The results reported significant decreases after treatment for CRP (mean of -0.62 mg/dL (95% CI: -0.84, -0,40), and a slight, but not statistically significant, reduction in IL-6 (mean of -1.31 pg/mL (95% CI: -2.86, 0.25). Conclusions. The ketogenic diet could contribute to modulating inflammation in obese and overweight subjects.
    Keywords:  CRP; inflammation; ketogenic diet; ketones; obesity
    DOI:  https://doi.org/10.3390/nu16234002
  5. Nutrients. 2024 Dec 06. pii: 4218. [Epub ahead of print]16(23):
    Effects of a 12 Week Ketogenic Diet Intervention on Obese and Overweight Females with Glucose and Lipid Metabolism Disturbance.
    Grzegorz Klonek, Grzegorz Zydek, Robert Roczniok, Mariusz Panek, Adam Zając, Małgorzata Magdalena Michalczyk.
       BACKGROUND/OBJECTIVES: We evaluated the effects of a 12-week hypocaloric ketogenic diet (KD) on glucose and lipid metabolism, as well as body mass, in overweight, obese, and healthy-weight females. One hundred adult females completed the study, including 64 obese (97.99 ± 11.48 kg), 23 overweight (75.50 ± 5.12 kg), and 11 with normal body mass (65.93 ± 3.40 kg). All participants followed a KD consisting of less than 30 g of carbohydrates, approximately 60 g of protein, and 140 g of fat per day (80% unsaturated and 20% saturated fat).
    METHODS: Glucose (Gl), insulin (I), glycated haemoglobin (HBA1c), HOMA-IR, triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) were measured before and after the intervention. Additionally, body mass (BM), BMI (Body Mass Index), waist circumference (WC), hip circumference (HC), and thigh circumference (TC) were recorded.
    RESULTS: After 12 weeks of the KD, significant improvements were observed in GL, I, TG, HDL-C, HOMA-IR across all groups. Also BM, BMI, TC, WC, and HC were significantly reduced in all participants. Notably, obese participants showed greater reductions in all variables compared to overweight and healthy-weight females.
    CONCLUSIONS: A 12-week KD led to more pronounced improvements in biochemical markers and body mass in obese females compared to other groups. A KD may be particularly beneficial for obese females with hyperglycaemia, hyperinsulinemia, and lipid profile disturbances.
    Keywords:  females; hyperglycaemia; ketogenic diet; obese; overweight
    DOI:  https://doi.org/10.3390/nu16234218
  6. J Clin Invest. 2024 Dec 16. pii: e176708. [Epub ahead of print]134(24):
    SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts.
    Leigh Goedeke, Yina Ma, Rafael C Gaspar, Ali Nasiri, Jieun Lee, Dongyan Zhang, Katrine Douglas Galsgaard, Xiaoyue Hu, Jiasheng Zhang, Nicole Guerrera, Xiruo Li, Traci LaMoia, Brandon T Hubbard, Sofie Haedersdal, Xiaohong Wu, John Stack, Sylvie Dufour, Gina Marie Butrico, Mario Kahn, Rachel J Perry, Gary W Cline, Lawrence H Young, Gerald I Shulman.
      Previous studies highlight the potential for sodium-glucose cotransporter type 2 (SGLT2) inhibitors (SGLT2i) to exert cardioprotective effects in heart failure by increasing plasma ketones and shifting myocardial fuel utilization toward ketone oxidation. However, SGLT2i have multiple in vivo effects and the differential impact of SGLT2i treatment and ketone supplementation on cardiac metabolism remains unclear. Here, using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology combined with infusions of [13C6]glucose or [13C4]βOHB, we demonstrate that acute SGLT2 inhibition with dapagliflozin shifts relative rates of myocardial mitochondrial metabolism toward ketone oxidation, decreasing pyruvate oxidation with little effect on fatty acid oxidation in awake rats. Shifts in myocardial ketone oxidation persisted when plasma glucose levels were maintained. In contrast, acute βOHB infusion similarly augmented ketone oxidation, but markedly reduced fatty acid oxidation and did not alter glucose uptake or pyruvate oxidation. After inducing heart failure, dapagliflozin increased relative rates of ketone and fatty acid oxidation, but decreased pyruvate oxidation. Dapagliflozin increased mitochondrial redox and reduced myocardial oxidative stress in heart failure, which was associated with improvements in left ventricular ejection fraction after 3 weeks of treatment. Thus, SGLT2i have pleiotropic effects on systemic and heart metabolism, which are distinct from ketone supplementation and may contribute to the long-term cardioprotective benefits of SGLT2i.
    Keywords:  Cardiology; Glucose metabolism; Intermediary metabolism; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/JCI176708
  7. Nature. 2024 Dec 18.
    A bile acid could explain how calorie restriction slows ageing.
    David A Sinclair.
      
    Keywords:  Ageing; Metabolism; Microbiome; Nutrition
    DOI:  https://doi.org/10.1038/d41586-024-04062-1
  8. J Clin Invest. 2024 Dec 16. pii: e187097. [Epub ahead of print]134(24):
    Beyond ketosis: the search for the mechanism underlying SGLT2-inhibitor benefit continues.
    Justin H Berger, Brian N Finck.
      Despite the impressive clinical benefits and widespread adoption of sodium glucose cotransporter 2 inhibitors (SGLT2i) to treat all classes of heart failure, their cardiovascular mechanisms of action are poorly understood. Proposed mechanisms range broadly and include enhanced ketogenesis, where the mild ketosis associated with SGLT2i use is presumed to be beneficial. However, in this issue of the JCI, carefully conducted metabolic flux studies by Goedeke et al. comparing the effects of SGLT2i and exogenous ketones suggest differential effects. Thus, the mechanisms of action for SGLT2i are likely pleiotropic, and further work is needed to fully understand their beneficial effects.
    DOI:  https://doi.org/10.1172/JCI187097
  9. Elife. 2024 Dec 20. pii: e105191. [Epub ahead of print]13
    Mapping mitochondrial aging.
    Alessandro Bitto.
      Measuring mitochondrial respiration in frozen tissue samples provides the first comprehensive atlas of how aging affects mitochondrial function in mice.
    Keywords:  aging; cellular respiration; computational biology; mitochondria; mouse; respiration atlas; sex; systems biology
    DOI:  https://doi.org/10.7554/eLife.105191
  10. Biomed Pharmacother. 2024 Dec 17. pii: S0753-3322(24)01660-3. [Epub ahead of print]182 117774
    1,3-butanediol administration as an alternative strategy to calorie restriction for neuroprotection - Insights into modulation of stress response in hippocampus of healthy rats.
    Luisa Cigliano, Francesca De Palma, Natasha Petecca, Gianluca Fasciolo, Giuliana Panico, Paola Venditti, Assunta Lombardi, Maria Stefania Spagnuolo.
      Ketogenic diet has a wide range of beneficial effects but presents practical limitations due to its low compliance, hence dietary supplements have been developed to induce ketosis without nutrient deprivation. The alcohol 1,3-butanediol (BD) is a promising molecule for its ability to induce ketosis, but its effects on brain have been investigated so far only in disease models, but never in physiological conditions. To support BD use to preserve brain health, the analysis of its activity is mandatory. Therefore, we investigated, in healthy rats, the effect of a fourteen-days BD-administration on the hippocampus, an area particularly vulnerable to oxidative and inflammatory damage. Since BD treatment has been reported to reduce energy intake, results were compared with those obtained from rats undergoing a restricted dietary regimen, isoenergetic with BD group (pair fed, PF). Reduced pro-inflammatory signaling pathways and glial activation were revealed in hippocampus of BD treated rats in comparison to control (C) and PF groups. ROS content and the extent of protein oxidative damage were lower in BD and PF groups than in C. Interestingly, higher amounts of nuclear factor erythroid 2-related factor 2 (Nrf2), decreased level of lipid hydroperoxides, lower susceptibility to oxidative insult, higher amounts of superoxide dismutase-2, glutathione reductase and glutathione peroxidase (GPx), and increased GPx activity were observed in BD animals. BD administration, but not dietary restriction, attenuated endoplasmic reticulum stress, reduced autophagic response activation, and was associated with an increase of both the neurotrophin BDNF and pre-synaptic proteins synaptophysin and synaptotagmin. Our results highlight that BD plays a neuroprotective role in healthy conditions, thus emerging as an effective strategy to support brain function without the need of implementing ketogenic nutritional interventions.
    Keywords:  Brain physiology; Dietary supplement; Neuroinflammation; Neuroprotection; Redox homeostasis; Stress response
    DOI:  https://doi.org/10.1016/j.biopha.2024.117774
  11. Int J Mol Sci. 2024 Nov 27. pii: 12740. [Epub ahead of print]25(23):
    Role of Fatty Acids β-Oxidation in the Metabolic Interactions Between Organs.
    Alexander V Panov, Vladimir I Mayorov, Sergey I Dikalov.
      In recent decades, several discoveries have been made that force us to reconsider old ideas about mitochondria and energy metabolism in the light of these discoveries. In this review, we discuss metabolic interaction between various organs, the metabolic significance of the primary substrates and their metabolic pathways, namely aerobic glycolysis, lactate shuttling, and fatty acids β-oxidation. We rely on the new ideas about the supramolecular structure of the mitochondrial respiratory chain (respirasome), the necessity of supporting substrates for fatty acids β-oxidation, and the reverse electron transfer via succinate dehydrogenase during β-oxidation. We conclude that ATP production during fatty acid β-oxidation has its upper limits and thus cannot support high energy demands alone. Meanwhile, β-oxidation creates conditions that significantly accelerate the cycle: glucose-aerobic glycolysis-lactate-gluconeogenesis-glucose. Therefore, glycolytic ATP production becomes an important energy source in high energy demand. In addition, lactate serves as a mitochondrial substrate after converting to pyruvate + H+ by the mitochondrial lactate dehydrogenase. All coupled metabolic pathways are irreversible, and the enzymes are organized into multienzyme structures.
    Keywords:  aerobic glycolysis; beta-oxidation; fatty acids; gluconeogenesis; lactate; metabolism; mitochondria; respirasome
    DOI:  https://doi.org/10.3390/ijms252312740
  12. Int Immunopharmacol. 2024 Dec 13. pii: S1567-5769(24)02343-9. [Epub ahead of print]146 113821
    Unraveling the priming phase of NLRP3 inflammasome activation: Molecular insights and clinical relevance.
    Yonghong Liao, Yueyao Kong, Hongyu Chen, Jing Xia, Jianjun Zhao, Yang Zhou.
      The NLRP3 inflammasome plays a pivotal role in the innate immune response. Its activation involves a two-step mechanism that consists of priming and activation. The priming of the NLRP3 inflammasome is a vital initial phase necessary for its activation and subsequent involvement in the immune response, though its understanding varies across studies. Recent research has identified key proteins that influence the priming process, revealing a sophisticated regulatory network. This review provides a comprehensive review of the priming phase of NLRP3 inflammasome activation, with a particular focus on the underlying molecular mechanisms, including transcriptional regulation, orchestration of the phosphorylation status, deubiquitination and the relationships with the inflammation-associated diseases. Understanding the intricacies of NLRP3 inflammasome priming not only elucidates fundamental aspects of immune regulation, but also provides potential avenues for therapeutic intervention in inflammatory diseases.
    Keywords:  Deubiquitination; NLRP3; Phosphorylation; Priming
    DOI:  https://doi.org/10.1016/j.intimp.2024.113821
  13. Annu Rev Physiol. 2024 Dec 10.
    Exercise as Mitochondrial Medicine: How Does the Exercise Prescription Affect Mitochondrial Adaptations to Training?
    David J Bishop, Matthew J-C Lee, Martin Picard.
      Mitochondria are multifaceted organelles with several life-sustaining functions beyond energy transformation, including cell signaling, calcium homeostasis, hormone synthesis, programmed cell death (apoptosis), and others. A defining aspect of these dynamic organelles is their remarkable plasticity, which allows them to sense, respond, and adapt to various stressors. In particular, it is well-established that the stress of exercise provides a powerful stimulus that can trigger transient or enduring changes to mitochondrial molecular features, activities, integrated functions, behaviors, and cell-dependent mitochondrial phenotypes. Evidence documenting the many beneficial mitochondrial adaptations to exercise has led to the notion of exercise as a mitochondrial medicine. However, as with other medicines, it is important to understand the optimal prescription (i.e., type, dose, frequency, duration). In this review, we build on a systematic biological framework that distinguishes between domains of mitochondrial biology to critically evaluate how different exercise prescription variables influence mitochondrial adaptations to training.
    DOI:  https://doi.org/10.1146/annurev-physiol-022724-104836
  14. J Appl Physiol (1985). 2024 Dec 16.
    Effects of contraction frequency during high-intensity training on fatigue resistance and aerobic adaptations in mouse skeletal muscle.
    Azuma Naito, Tatsuya Sato, Iori Kimura, Nao Tokuda, Nao Yamauchi, Hiroyori Fusagawa, Takashi Yamada.
      In high-intensity and sprint interval training, the frequency of contractions is typically higher compared to moderate-intensity continuous training, but it remains unclear whether this contributes to the effective increase in fatigue resistance mechanisms. Here, we investigated the role of contraction frequency in high-intensity training on endurance adaptations of mouse skeletal muscle. Male C57BL/6 mice were divided into groups based on high (0.25 s contraction every 0.5 s) and low (0.25 s contraction every 4.5 s) contraction frequencies, with either 360 contractions per session (Hi360 and Lo360) or 30 contractions per session (Hi30 and Lo30). The plantar flexor muscles were stimulated using in vivo supramaximal electrical stimulation, where all muscle fibers were maximally activated, every other day for 5 weeks. In both the Hi360 and Lo360 groups, where force production declined to less than 40% of the initial value during the training session, muscle endurance, as well as mitochondrial content and respiratory capacity, were increased to a similar extent. In contrast, the rate of torque decline during the training session was more pronounced in the Hi30 group compared to the Lo30 group. In response, the Hi30 group, but not the Lo30 group, exhibited increased fatigue resistance and mitochondrial respiration, which was accompanied by increased PGC-1α expression and an activation of AMPK/Ulk1 pathway. These data suggest that the frequency of contractions is a critical factor in determining the efficient enhancement of mitochondrial respiratory capacity and muscle endurance through high-intensity training, presumably due to promotion of mitochondrial quality control.
    Keywords:  contraction frequency; fatigue resistance; high-intensity interval training; mitochondria
    DOI:  https://doi.org/10.1152/japplphysiol.00530.2024
  15. Elife. 2024 Dec 20. pii: RP96926. [Epub ahead of print]13
    Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.
    Dylan C Sarver, Muzna Saqib, Fangluo Chen, G William Wong.
      Organ function declines with age, and large-scale transcriptomic analyses have highlighted differential aging trajectories across tissues. The mechanism underlying shared and organ-selective functional changes across the lifespan, however, still remains poorly understood. Given the central role of mitochondria in powering cellular processes needed to maintain tissue health, we therefore undertook a systematic assessment of respiratory activity across 33 different tissues in young (2.5 months) and old (20 months) mice of both sexes. Our high-resolution mitochondrial respiration atlas reveals: (1) within any group of mice, mitochondrial activity varies widely across tissues, with the highest values consistently seen in heart, brown fat, and kidney; (2) biological sex is a significant but minor contributor to mitochondrial respiration, and its contributions are tissue-specific, with major differences seen in the pancreas, stomach, and white adipose tissue; (3) age is a dominant factor affecting mitochondrial activity, especially across most brain regions, different fat depots, skeletal muscle groups, eyes, and different regions of the gastrointestinal tract; (4) age effects can be sex- and tissue-specific, with some of the largest effects seen in pancreas, heart, adipose tissue, and skeletal muscle; and (5) while aging alters the functional trajectories of mitochondria in a majority of tissues, some are remarkably resilient to age-induced changes. Altogether, our data provide the most comprehensive compendium of mitochondrial respiration and illuminate functional signatures of aging across diverse tissues and organ systems.
    Keywords:  aging; computational biology; mitochondria; mouse; respiration atlas; sex; systems biology
    DOI:  https://doi.org/10.7554/eLife.96926
  16. FASEB J. 2024 Dec 13. 38(24): e70235
    Time-of-day control of mitochondria regulates NLRP3 inflammasome activation in macrophages.
    James R O'Siorain, Shannon L Cox, Cloé Payet, Frances K Nally, Yan He, Tabea T Drewinksi, Oran D Kennedy, Jennifer K Dowling, Mark Mellett, James O Early, Annie M Curtis.
      Macrophages are innate immune cells that orchestrate the process of inflammation, which varies across time of day. This ensures appropriate biological timing of the immune response with the external environment. The NLRP3 inflammasome mediates IL-1-family cytokine release via pyroptosis. Mitochondria play a multifaceted role regulating NLRP3 inflammasome activity. Mitochondria exhibit distinct metabolic changes across time of day, which are influenced by clock genes. However, whether the macrophage clock regulates the NLRP3 inflammasome via mitochondrial control remains unclear. We find heightened mitochondrial membrane potential (Δψm) and enhanced NLRP3 inflammasome activation from peritoneal exudate cells (PECs) isolated at circadian time (CT) 12 compared to CT 0. In vitro time-of-day synchronization of bone-marrow derived macrophages (BMDMs) induced time-dependent differences in NLRP3 inflammasome activation. Myeloid-specific Bmal1-deletion enhanced NLRP3 inflammasome activity in PECs at CT0 and in unsynchronized BMDMs compared to controls. Pharmacologically disrupting Δψm in synchronized cells reduced NLRP3 inflammasome activation to comparable levels, and the same occurred with Bmal1-deletion. These results further demonstrate circadian clock timing of the NLRP3 inflammasome, which is dependent on mitochondrial function and driven through the circadian gene Bmal1.
    Keywords:  NLRP3 inflammasome; circadian rhythms; macrophages; mitochondria; pyroptosis
    DOI:  https://doi.org/10.1096/fj.202400508RR
  17. Biochim Biophys Acta Bioenerg. 2024 Dec 13. pii: S0005-2728(24)00502-4. [Epub ahead of print]1866(2): 149532
    Acute treadmill exercise induces mitochondrial unfolded protein response in skeletal muscle of male rats.
    Ibrahim Turkel, Gokhan Burcin Kubat, Tugba Fatsa, Ozgu Acet, Berkay Ozerklig, Burak Yazgan, Gulcin Simsek, Keshav K Singh, Sukran Nazan Kosar.
      Mitochondria are often referred to as the energy centers of the cell and are recognized as key players in signal transduction, sensing, and responding to internal and external stimuli. Under stress conditions, the mitochondrial unfolded protein response (UPRmt), a conserved mitochondrial quality control mechanism, is activated to maintain mitochondrial and cellular homeostasis. As a physiological stimulus, exercise-induced mitochondrial perturbations trigger UPRmt, coordinating mitochondria-to-nucleus communication and initiating a transcriptional program to restore mitochondrial function. The aim of this study was to evaluate the UPRmt signaling response to acute exercise in skeletal muscle. Male rats were subjected to acute treadmill exercise at 25 m/min for 60 min on a 0 % grade. Plantaris muscles were collected from both sedentary and exercise groups at various times: immediately (0), and at 1, 3, 6, 12, and 24 h post-exercise. Reactive oxygen species (ROS) production was assessed using hydrogen peroxide assay and dihydroethidium staining. Additionally, the mRNA and protein expression of UPRmt markers were measured using ELISA and real-time PCR. Mitochondrial activity was assessed using succinate dehydrogenase (SDH) and cytochrome c oxidase (COX) staining. Our results demonstrated that acute exercise increased ROS production and upregulated UPRmt markers at both gene and protein levels. Moreover, skeletal muscle exhibited an increase in mitochondrial activity in response to exercise, as indicated by SDH and COX staining. These findings suggest that acute treadmill exercise is sufficient to induce ROS production, activate UPRmt signaling, and enhance mitochondrial activity in skeletal muscle, expanding our understanding of mitochondrial adaptations to exercise.
    Keywords:  Exercise; Mitochondria; Mitochondrial proteostasis; Mitochondrial unfolded protein response; Skeletal muscle; UPR(mt)
    DOI:  https://doi.org/10.1016/j.bbabio.2024.149532
  18. Subcell Biochem. 2024 ;107 63-90
    NAD+ Boosting Strategies.
    Jared Rice, Sofie Lautrup, Evandro F Fang.
      Nicotinamide adenine dinucleotide (oxidized form, NAD+) serves as a co-substrate and co-enzyme in cells to execute its key roles in cell signalling pathways and energetic metabolism, arbitrating cell survival and death. It was discovered in 1906 by Arthur Harden and William John Young in yeast extract which could accelerate alcohol fermentation. NAD acts as an electron acceptor and cofactor throughout the processes of glycolysis, Tricarboxylic Acid Cycle (TCA), β oxidation, and oxidative phosphorylation (OXPHOS). NAD has two forms: NAD+ and NADH. NAD+ is the oxidising coenzyme that is reduced when it picks up electrons. NAD+ levels steadily decline with age, resulting in an increase in vulnerability to chronic illness and perturbed cellular metabolism. Boosting NAD+ levels in various model organisms have resulted in improvements in healthspan and lifespan extension. These results have prompted a search for means by which NAD+ levels in the body can be augmented by both internal and external means. The aim of this chapter is to provide an overview of NAD+, appraise clinical evidence of its importance and success in potentially extending health- and lifespan, as well as to explore NAD+ boosting strategies.
    Keywords:  Ageing; Caloric restriction; NAD+; Neurodegeneration; Nicotinamide mononucleotide; Nicotinamide riboside; Oxidative stress; Supplementation
    DOI:  https://doi.org/10.1007/978-3-031-66768-8_4
  19. NPJ Metab Health Dis. 2024 ;2(1): 37
    Too old for healthy aging? Exploring age limits of longevity treatments.
    Prerana Shrikant Chaudhari, Maria A Ermolaeva.
      It is well documented that aging elicits metabolic failures, while poor metabolism contributes to accelerated aging. Metabolism in general, and energy metabolism in particular are also effective entry points for interventions that extend lifespan and improve organ function during aging. In this review, we discuss common metabolic remedies for healthy aging from the angle of their potential age-specificity. We demonstrate that some well-known metabolic treatments are mostly effective in young and middle-aged organisms, while others maintain high efficacy independently of age. The mechanistic basis of presence or lack of the age limitations is laid out and discussed.
    Keywords:  Energy metabolism; Metabolism; Mitochondria; Physiology
    DOI:  https://doi.org/10.1038/s44324-024-00040-3
  20. Redox Biol. 2024 Dec 12. pii: S2213-2317(24)00445-2. [Epub ahead of print]79 103467
    Sarcopenic obesity is attenuated by E-syt1 inhibition via improving skeletal muscle mitochondrial function.
    Chao Song, Wu Zheng, Guoming Liu, Yiyang Xu, Zhibo Deng, Yu Xiu, Rongsheng Zhang, Linhai Yang, Yifei Zhang, Guoyu Yu, Yibin Su, Jun Luo, Bingwei He, Jie Xu, Hanhao Dai.
      In aging and metabolic disease, sarcopenic obesity (SO) correlates with intramuscular adipose tissue (IMAT). Using bioinformatics analysis, we found a potential target protein Extended Synaptotagmin 1 (E-syt1) in SO. To investigate the regulatory role of E-syt1 in muscle metabolism, we performed in vivo and in vitro experiments through E-syt1 loss- and gain-of-function on muscle physiology. When E-syt1 is overexpressed in vitro, myoblast proliferation, differentiation, mitochondrial respiration, biogenesis, and mitochondrial dynamics are impaired, which were alleviated by the silence of E-syt1. Furthermore, overexpression of E-syt1 inhibited mitophagic flux. Mechanistically, E-syt1 overexpression leads to mitochondrial calcium overload and mitochondrial ROS burst, inhibits the fusion of mitophagosomes with lysosomes, and impedes the acidification of lysosomes. Animal experiments demonstrated the inhibition of E-syt1 increased the capacity of endurance exercise, muscle mass, mitochondrial function, and oxidative capacity of the muscle fibers in OVX mice. These findings establish E-syt1 as a novel contributor to the pathogenesis of skeletal muscle metabolic disorders in SO. Consequently, targeting E-syt1-induced dysfunction may serve as a viable strategy for attenuating SO.
    Keywords:  E-syt1; Mitochondria; Mitophagy; Myogenesis; Sarcopenic obesity
    DOI:  https://doi.org/10.1016/j.redox.2024.103467
  21. Cell Mol Biol Lett. 2024 Dec 18. 29(1): 153
    Inter- and intracellular mitochondrial communication: signaling hubs in aging and age-related diseases.
    Meng Zhang, Jin Wei, Chang He, Liutao Sui, Chucheng Jiao, Xiaoyan Zhu, Xudong Pan.
      Mitochondria are versatile and complex organelles that can continuously communicate and interact with the cellular milieu. Deregulated communication between mitochondria and host cells/organelles has significant consequences and is an underlying factor of many pathophysiological conditions, including the process of aging. During aging, mitochondria lose function, and mitocellular communication pathways break down; mitochondrial dysfunction interacts with mitochondrial dyscommunication, forming a vicious circle. Therefore, strategies to protect mitochondrial function and promote effective communication of mitochondria can increase healthy lifespan and longevity, which might be a new treatment paradigm for age-related disorders. In this review, we comprehensively discuss the signal transduction mechanisms of inter- and intracellular mitochondrial communication, as well as the interactions between mitochondrial communication and the hallmarks of aging. This review emphasizes the indispensable position of inter- and intracellular mitochondrial communication in the aging process of organisms, which is crucial as the cellular signaling hubs. In addition, we also specifically focus on the status of mitochondria-targeted interventions to provide potential therapeutic targets for age-related diseases.
    Keywords:  Age-related diseases; Aging; Mitochondrial communication; Mitochondrial dysfunction; Signaling hubs
    DOI:  https://doi.org/10.1186/s11658-024-00669-4
  22. J Cell Sci. 2024 Dec 15. pii: jcs262071. [Epub ahead of print]137(24):
    Fantastic proteins and where to find them - histones, in the nucleus and beyond.
    Johanna Grinat, Noah P Shriever, Maria A Christophorou.
      Animal genomes are packaged into chromatin, a highly dynamic macromolecular structure of DNA and histone proteins organised into nucleosomes. This accommodates packaging of lengthy genomic sequences within the physical confines of the nucleus while also enabling precise regulation of access to genetic information. However, histones existed before chromatin and have lesser-known functions beyond genome regulation. Most notably, histones are potent antimicrobial agents, and the release of chromatin to the extracellular space is a defence mechanism nearly as ancient and widespread as chromatin itself. Histone sequences have changed very little throughout evolution, suggesting the possibility that some of their 'non-canonical' functions are at play in parallel or in concert with their genome regulatory functions. In this Review, we take an evolutionary perspective of histone, nuclear chromatin and extracellular chromatin biology and describe the known extranuclear and extracellular functions of histones. We detail molecular mechanisms of chromatin release and extracellular chromatin sensing, and we discuss their roles in physiology and disease. Finally, we present evidence and give a perspective on the potential of extracellular histones to act as bioactive, cell modulatory factors.
    Keywords:  Chromatin; Evolution; Extracellular; Histones; Post-translational modifications; Signalling
    DOI:  https://doi.org/10.1242/jcs.262071
  23. Transl Exerc Biomed. 2024 Sep;1(3-4): 183-194
    Impact of exercise and fasting on mitochondrial regulators in human muscle.
    Eveline S Menezes, Hashim Islam, Benjamin B Arhen, Craig A Simpson, Chris McGlory, Brendon J Gurd.
       Objectives: To investigate the impact of acute energetic stress (acute HIIE and fasting) on ERRγ, PPARβ, NR1D1, NR4A1, and TFEB in human skeletal muscle.
    Methods: The current study performed secondary analyses using muscle biopsy samples from two previously published studies: study 1) leg muscle biopsies from nine men and eight women were obtained pre and 3 h following acute high-intensity interval cycling exercise (HIIE); study 2) leg muscle biopsies were obtained from nine men pre-, during, and post-an 8 h fast with or without 2 h of arm ergometer exercise. RT-PCR was performed on samples from each study to determine the mRNA expression of ERRγ, PPARβ, NR1D1, NR4A1, and TFEB. Additionally, we retrieved data from meta-analyzed human muscle gene expression using the publicly available database MetaMex.
    Results: PGC-1α (p<0.01, d=1.98) and NR4A1 (p<0.01, d=1.36) mRNA expression significantly increased while TFEB (p≤0.05, d=0.70) decreased following HIIE. Significant decreases in NR4A1 and NR1D1 mRNA expression were observed following an 8 h fast. Our MetaMex analyses revealed significant increases (p<0.05) in PGC-1α and NR4A1 expression following aerobic and resistance exercise, and in PPARβ expression following resistance exercise.
    Conclusions: Our data indicate that acute HIIE stimulates increases in NR4A1 and PGC-1α and decreases in TFEB mRNA expression in human skeletal muscle. Additionally, a short term (8 h) fast reduced the mRNA expression of the transcriptional regulators NR4A1 and NR1D1 - potentially as a mechanism of decreasing mitochondrial biogenesis to reduce energy expenditure during a period of restricted energy availability.
    Keywords:  aerobic exercise; caloric restriction; food deprivation; muscle remodeling; transcriptional regulators
    DOI:  https://doi.org/10.1515/teb-2024-0014
  24. Poult Sci. 2024 Dec 11. pii: S0032-5791(24)01235-5. [Epub ahead of print]104(1): 104657
    FKBP5 as a key regulator of metabolic processes in birds: Insights from chicken pectoral muscle.
    Pengfei Du, Xiangli Zhang, Yao Zhu, Ziyang Wang, Xuemeng Si, Huaiyong Zhang, Yanqun Huang, Wen Chen.
      FK506-binding protein 5 (FKBP5) is a negative regulator of the glucocorticoid response and may play an important role in regulating metabolic homeostasis in birds. However, limited information is available regarding its role in avian species. This study aimed to clarify the spatiotemporal characteristics of chicken FKBP5 and investigate the effects of exogenous stimuli on its expression. Real-time quantitative PCR (RT-qPCR) was utilized to analyze the spatiotemporal expression patterns of FKBP5 in chickens. Additionally, the impact of exogenous stimuli, including fasting, energy restriction, and insulin/pyruvate/glucose injections, on FKBP5 expression in the pectoral muscle was investigated. The results showed that FKBP5 is broadly expressed in various bird tissues, with dominant expression in insulin-sensitive tissues. The FKBP5 levels in birds are dramatically modulated during development in insulin-sensitive tissues, with the highest expression observed in striated muscle and liver at embryonic day 19 (E19) (P < 0.01). The basal level of FKBP5 in the pectoral muscle of broilers is higher than that in Silky chickens. Insulin administration leads to a rapid drop in blood glucose levels in both breeds, with a slower recovery in AA broilers (P < 0.01). However, FKBP5 expression in the pectoral muscle initially shows a slight drop, followed by a sharp increase over time after insulin administration (P < 0.01). Additionally, breed heterogeneity in FKBP5 expression was observed in the pectoral muscle upon insulin stimulation, with broilers showing stronger insulin sensitivity compared to Silky chickens. A 24-hour fasting period downregulated blood glucose levels (P < 0.01) and FKBP5 expression in the pectoral muscle of AA broilers (P < 0.01). A 30% energy restriction over three weeks slightly reduced blood glucose levels (P = 0.075) and significantly decreased FKBP5 levels in the pectoralis muscle of broilers. In addition, pyruvate increased blood glucose and pectoralis FKBP5 transcription levels at 60 min (P < 0.01), whereas glucose increased blood glucose levels but had no effect on FKBP5 expression. Overall analysis showed a negative correlation between FKBP5 expression in the pectoral muscle and blood glucose levels (ρ = -0.405, P < 0.001). In conclusion, FKBP5 is a key player in the metabolic regulation of birds, with its expression being highly dynamic and tissue-specific. Insulin regulates FKBP5 expression in pectoral muscles in a time-dependent manner, while pyruvate increases FKBP5 levels and fasting/energy restriction reduces FKBP5 mRNA expression in the pectoral muscles.
    Keywords:  Blood glucose; Breed heterogeneity; Correlation; Insulin sensitivity; Pectoral muscle
    DOI:  https://doi.org/10.1016/j.psj.2024.104657
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