bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2025–02–02
thirteen papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello
  1. Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation.
  2. Comprehensive Overview of Ketone Bodies in Cancer Metabolism: Mechanisms and Application.
  3. Targeting Ketone Body Metabolism Improves Cardiac Function and Hemodynamics in Patients With Heart Failure: A Systematic Review and Meta-Analysis.
  4. Endurance training and pyruvate dehydrogenase kinase 4 (PDK4) inhibition combination is superior to each one alone in attenuating hyperketonemia/ketoacidosis in diabetic rats.
  5. The roles of mitochondria in global and local intracellular calcium signalling.
  6. Epigenetic modification increases skeletal muscle resilience to metabolic stress.
  7. The Metabolism of Creatinine and Its Usefulness to Evaluate Kidney Function and Body Composition in Clinical Practice.
  8. Intermittent fasting is good for losing (some) weight.
  9. Optimizing oral 3-hydroxybutyrate dosage using pharmacokinetic model to improve cognitive function and mood in healthy subjects.
  10. Mitochondrial dynamics: molecular mechanism and implications in endometriosis.
  11. Tissue-resident skeletal muscle macrophages promote recovery from viral pneumonia-induced sarcopenia in normal aging.
  12. Mitochondrial Ribosomal Proteins and Cancer.
  13. Sodium butyrate activates the extrinsic and intrinsic apoptotic processes in murine cementoblasts.
  1. Sci Adv. 2025 Jan 31. 11(5): eads0535
    Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation.
    Eric D Queathem, Zahra Moazzami, David B Stagg, Alisa B Nelson, Kyle Fulghum, Abdirahman Hayir, Alisha Seay, Jacob R Gillingham, D André d'Avignon, Xianlin Han, Hai-Bin Ruan, Peter A Crawford, Patrycja Puchalska.
      Ketogenesis is a dynamic metabolic conduit supporting hepatic fat oxidation particularly when carbohydrates are in short supply. Ketone bodies may be recycled into anabolic substrates, but a physiological role for this process has not been identified. Here, we use mass spectrometry-based 13C-isotope tracing and shotgun lipidomics to establish a link between hepatic ketogenesis and lipid anabolism. Unexpectedly, mouse liver and primary hepatocytes consumed ketone bodies to support fatty acid biosynthesis via both de novo lipogenesis (DNL) and polyunsaturated fatty acid (PUFA) elongation. While an acetoacetate intermediate was not absolutely required for ketone bodies to source DNL, PUFA elongation required activation of acetoacetate by cytosolic acetoacetyl-coenzyme A synthetase (AACS). Moreover, AACS deficiency diminished free and esterified PUFAs in hepatocytes, while ketogenic insufficiency depleted PUFAs and increased liver triacylglycerols. These findings suggest that hepatic ketogenesis influences PUFA metabolism, representing a molecular mechanism through which ketone bodies could influence systemic physiology and chronic diseases.
    DOI:  https://doi.org/10.1126/sciadv.ads0535
  2. Biomedicines. 2025 Jan 16. pii: 210. [Epub ahead of print]13(1):
    Comprehensive Overview of Ketone Bodies in Cancer Metabolism: Mechanisms and Application.
    Ziyuan Liang, Lixian Deng, Xiaoying Zhou, Zhe Zhang, Weilin Zhao.
      Reprogramming energy metabolism is pivotal to tumor development. Ketone bodies (KBs), which are generated during lipid metabolism, are fundamental bioactive molecules that can be modulated to satisfy the escalating metabolic needs of cancer cells. At present, a burgeoning body of research is concentrating on the metabolism of KBs within tumors, investigating their roles as signaling mediators, drivers of post-translational modifications, and regulators of inflammation and oxidative stress. The ketogenic diet (KD) may enhance the sensitivity of various cancers to standard therapies, such as chemotherapy and radiotherapy, by exploiting the reprogrammed metabolism of cancer cells and shifting the metabolic state from glucose reliance to KB utilization, rendering it a promising candidate for adjunct cancer therapy. Nonetheless, numerous questions remain regarding the expression of key metabolic genes across different tumors, the regulation of their activities, and the impact of individual KBs on various tumor types. Further investigation is imperative to resolve the conflicting data concerning KB synthesis and functionality within tumors. This review aims to encapsulate the intricate roles of KBs in cancer metabolism, elucidating a comprehensive grasp of their mechanisms and highlighting emerging clinical applications, thereby setting the stage for future investigations into their therapeutic potential.
    Keywords:  ketogenic diet; ketone bodies; metabolism; therapeutic approach; tumor
    DOI:  https://doi.org/10.3390/biomedicines13010210
  3. Nutr Rev. 2025 Jan 28. pii: nuae179. [Epub ahead of print]
    Targeting Ketone Body Metabolism Improves Cardiac Function and Hemodynamics in Patients With Heart Failure: A Systematic Review and Meta-Analysis.
    Tingting Lv, Chunyan Liu, Shitian Guo, Menglu Wu, Xiang Wang, Ziyi Zhang, Jiedong Zhou, Yiying Yao, Zeyu Shen, Juntao Yang, Shijia Sun, Zheng Liu, Jufang Chi.
       CONTEXT: The impacts of elevated ketone body levels on cardiac function and hemodynamics in patients with heart failure (HF) remain unclear.
    OBJECTIVE: The effects of ketone intervention on these parameters in patients with HF were evaluated quantitatively in this meta-analysis.
    DATA SOURCES: We searched the PubMed, Cochrane Library, and Embase databases for relevant studies published from inception to April 13, 2024. Ketone therapy included ketone ester and β-hydroxybutyrate intervention.
    DATA EXTRACTION: Seven human studies were included for the quantitative analysis.
    DATA ANALYSIS: Our results showed that ketone therapy significantly improved left ventricular ejection fraction (standardized mean difference, 0.52 [95% CI, 0.25-0.80]; I2 = 0%), cardiac output (0.84 [95% CI, 0.36-1.32]; I2 = 68%) and stroke volume (0.47 [95% CI, 0.10-0.84]; I2 = 39%), and significantly reduced systemic vascular resistance (-0.92 [95% CI, -1.52 to -0.33]; I2 = 74%) without influencing mean arterial pressure (-0.09 [95% CI: -0.40 to 0.22]; I2 = 0%) in patients with HF. Subgroup analysis revealed that the enhanced cardiac function and favorable hemodynamic effects of ketone therapy were also applicable to individuals without HF.
    CONCLUSIONS: Ketone therapy may significantly improve cardiac systolic function and hemodynamics in patients with HF and in patients without HF, suggesting it may be a promising treatment for patients with HF and also a beneficial medical strategy for patients without HF or healthy individuals.
    Keywords:  cardiac function and hemodynamics; heart failure; ketone body metabolism; meta-analysis
    DOI:  https://doi.org/10.1093/nutrit/nuae179
  4. Iran J Basic Med Sci. 2025 ;28(1): 80-86
    Endurance training and pyruvate dehydrogenase kinase 4 (PDK4) inhibition combination is superior to each one alone in attenuating hyperketonemia/ketoacidosis in diabetic rats.
    Hamed Rezaeinasab, Abdolhamid Habibi, Ramin Rezaei, Aref Basereh, Salva Reverentia Yurista, Kayvan Khoramipour.
       Objectives: While ketone bodies are not the main heart fuel, exercise may increase their uptake. Objectives: This study aimed to investigate the effect of 6-week endurance training and Pyruvate dehydrogenase kinase 4 )PDK4( inhibition on ketone bodies metabolism in the heart of diabetic rats with emphasis on the role of Peroxisome proliferator-activated receptor-gamma coactivator PGC-1alpha (PGC-1α).
    Materials and Methods: Sixty male Wistar rats were divided into eight groups: healthy control group (CONT), endurance training group (TRA), diabetic group (DM), DM + EX group, Dichloroacetate (DCA) group, DM + DCA group, TRA + DCA group, and DM + TRA + DCA group. Diabetes was induced using streptozotocin (STZ). The animals in training groups ran on the treadmill for six weeks (30-50 min running at 20-30 m/min). After the training period, molecular markers for mitochondrial biogenesis and ketone metabolism were assessed in the heart. Circulating ß-hydroxybutyrate (ßOHB) and Acetylacetonate (AcAc) levels were also measured.
    Results: Our results showed that 6-week endurance training increased the cardiac expression of PGC-1α, 3-oxoacid CoA-transferase 1 (OXCT1), and Acetyl-CoA Acetyltransferase 1 (ACAT1) and reduced beta-hydroxybutyrate dehydrogenase1 (BDH1) expression (P≤0.05). In addition, exercise and DCA usage significantly decreased PDK4 gene expression, ßOHB, and AcAc blood levels (P≤0.05). Furthermore, the combination of 6-week endurance training and DCA supplementation led to more reduction in PDFK4 gene expression, ßOHB, and AcAc blood levels.
    Conclusion: Six-week endurance training and DCA supplementation could safely improve ketone body metabolism in the heart, ultimately reducing hyperketonemia/ketoacidosis in diabetic rats.
    Keywords:  Dietary supplements; Endurance training; Gene expression; Ketone bodies; Ketosis; Pyruvate dehydrogenase - kinase 4
    DOI:  https://doi.org/10.22038/ijbms.2024.79864.17305
  5. Nat Rev Mol Cell Biol. 2025 Jan 27.
    The roles of mitochondria in global and local intracellular calcium signalling.
    Benjamín Cartes-Saavedra, Arijita Ghosh, György Hajnóczky.
      Activation of Ca2+ channels in Ca2+ stores in organelles and the plasma membrane generates cytoplasmic calcium ([Ca2+]c) signals that control almost every aspect of cell function, including metabolism, vesicle fusion and contraction. Mitochondria have a high capacity for Ca2+ uptake and chelation, alongside efficient Ca2+ release mechanisms. Still, mitochondria do not store Ca2+ in a prolonged manner under physiological conditions and lack the capacity to generate global [Ca2+]c signals. However, mitochondria take up Ca2+ at high local [Ca2+]c signals that originate from neighbouring organelles, and also during sustained global elevations of [Ca2+]c. Accumulated Ca2+ in the mitochondria stimulates oxidative metabolism and upon return to the cytoplasm, can produce spatially confined rises in [Ca2+]c to exert control over processes that are sensitive to Ca2+. Thus, the mitochondrial handling of [Ca2+]c is of physiological relevance. Furthermore, dysregulation of mitochondrial Ca2+ handling can contribute to debilitating diseases. We discuss the mechanisms and relevance of mitochondria in local and global calcium signals.
    DOI:  https://doi.org/10.1038/s41580-024-00820-1
  6. Nat Metab. 2025 Jan 27.
    Epigenetic modification increases skeletal muscle resilience to metabolic stress.
      
    DOI:  https://doi.org/10.1038/s42255-024-01211-8
  7. Biomolecules. 2025 Jan 01. pii: 41. [Epub ahead of print]15(1):
    The Metabolism of Creatinine and Its Usefulness to Evaluate Kidney Function and Body Composition in Clinical Practice.
    Marcela Ávila, Mariana G Mora Sánchez, Alma Sofía Bernal Amador, Ramón Paniagua.
      Serum creatinine levels are the most used clinical marker to estimate renal function as the glomerular function rate because it is simple, fast, and inexpensive. However, creatinine has limitations, as its levels can be influenced by factors such as advanced age, physical activity, protein-rich diets, male gender, medications, and ethnicity. Serum cystatin C and its combination with serum creatinine may serve as an alternative since these factors do not affect it. Most creatinine synthesis occurs in the muscles, making it a valuable marker for assessing lean body mass within body composition. This measurement is crucial for evaluating and monitoring nutritional status in patients with chronic kidney disease. This review aimed to discuss the literature on creatinine metabolism, its advantages and disadvantages in assessing renal function, and its utility in measuring lean body mass. The variability in the creatinine generation rate among individuals should be considered when assessing the glomerular function rate.
    Keywords:  CKD biomarkers; chronic kidney disease; creatinine kinetics; creatinine metabolism; cystatin C; glomerular filtration rate; muscle mass markers
    DOI:  https://doi.org/10.3390/biom15010041
  8. Nat Med. 2025 Jan 28.
    Intermittent fasting is good for losing (some) weight.
    Olivia M Altonji, Courtney M Peterson.
      
    DOI:  https://doi.org/10.1038/s41591-024-03468-8
  9. Front Nutr. 2024 ;11 1470331
    Optimizing oral 3-hydroxybutyrate dosage using pharmacokinetic model to improve cognitive function and mood in healthy subjects.
    Kentaro Nishioka, Takahiro Ishimoto, Mariko Sato, Ruki Yasuda, Yumi Nakamura, Hiroshi Watanabe, Toshihide Suzuki, Yudai Araragi, Yukio Kato, Ken-Ichi Yoshida, Norihito Murayama.
       Introduction: The brain uses ketones, mainly 3-hydroxybutyrate (3-HB), as an alternative energy source. Therefore, oral intake of 3-HB may help maintain brain health. Previous studies indicated that achieving a maximum concentration (Cmax) of 3-HB in plasma at 0.28 mM could initiate ketone metabolism in the brain; we hypothesized that attaining this Cmax would improve brain health.
    Methods: We aimed to demonstrate the efficacy of an optimized single oral dose of 3-HB on cognitive function and mood through two clinical studies: a pharmacokinetic study and an efficacy study. In the pharmacokinetic study, healthy subjects were ingested 2 and 4 g of 3-HB to construct a compartment model to predict the minimum oral dose of 3-HB needed to achieve the target Cmax. In the efficacy study, a randomized, double-blinded, and placebo-controlled crossover trial, the effects of 3-HB at the predicted doses on cognitive function and mood in healthy subjects were assessed by a serial arithmetic test (SAT), the cognitrax, the profile of mood states 2nd edition (POMS2), and fatigue visual analog scale (VAS).
    Results: In the pharmacokinetic study, a one-compartment model that includes saturable and non-saturable absorption pathways, constant biosynthesis, and the linear elimination of 3-HB after oral administration were constructed. The model principally reflected the observed serum 3-HB concentrations profiles and predicted a minimum dose of 3.5 g needed to achieve the target Cmax. In the efficacy study, although no significant difference was observed in any cognitive domains assessed by the Cognitrax, total responses and correct answers in the SAT were significantly improved in the active group receiving 3.5 g of 3-HB compared to the placebo group. Regarding the POMS2, confusion-bewilderment, fatigue-inertia, vigor-activity, and total mood disturbance scales were significantly improved in the active group compared to the placebo group. Additionally, fatigue VAS were also significantly improved in the active group compared to the placebo group.
    Discussion: We successfully established a one-compartment model for oral 3-HB intake and demonstrated partial efficacy on cognitive function and broad efficacy on mood in healthy subjects with a single oral dose of 3.5 g of 3-HB optimized by the model.
    Clinical trial registration: https://www.umin.ac.jp/ctr/index-j.htm, identifier [UMIN000042095, UMIN000046666].
    Keywords:  3-hydroxybutyrate; beta-hydroxybutyrate; brain energy; cognitive function; compartment model; ketone; mood
    DOI:  https://doi.org/10.3389/fnut.2024.1470331
  10. Biochimie. 2025 Jan 28. pii: S0300-9084(25)00023-9. [Epub ahead of print]
    Mitochondrial dynamics: molecular mechanism and implications in endometriosis.
    Ylenia Marino, Francesca Inferrera, Tiziana Genovese, Salvatore Cuzzocrea, Roberta Fusco, Rosanna Di Paola.
      Endometriosis affects about 10% of women of reproductive age, leading to a disabling gynecologic condition. Chronic pain, inflammation, and oxidative stress have been identified as the molecular pathways involved in the progression of this disease, although its precise etiology remains uncertain. Although mitochondria are considered crucial organelles for cellular activity, their dysfunction has been linked to the development of this disease. The purpose of this review is to examine the functioning of the mitochondrion in endometriosis: in particular, we focused on the mitochondrial dynamics of biogenesis, fusion, and fission. Since excessive mitochondrial activity is reported to affect cell proliferation, we also considered mitophagy as a mechanism involved in limiting disease development. To better understand mitochondrial activity, we also considered alterations in circadian rhythms, the gut microbiome, and estrogen receptors: indeed, these mechanisms are also involved in the development of endometriosis. In addition, we focused on recent research about the impact of numerous substances on mitochondrial activity; some of them may offer a future breakthrough in endometriosis treatment by acting on mitochondria and inhibiting cell proliferation.
    Keywords:  Endometriosis; Inflammation; Mitochondria; Mitochondrial Dysfunction; Oxidative stress
    DOI:  https://doi.org/10.1016/j.biochi.2025.01.012
  11. bioRxiv. 2025 Jan 14. pii: 2025.01.09.631996. [Epub ahead of print]
    Tissue-resident skeletal muscle macrophages promote recovery from viral pneumonia-induced sarcopenia in normal aging.
    Constance E Runyan, Lucy Luo, Lynn C Welch, Ziyan Lu, Fei Chen, Maxwell J Schleck, Radmila A Nafikova, Rogan A Grant, Raul Piseaux Aillon, Karolina J Senkow, Elsie G Bunyan, William T Plodzeen, Hiam Abdala-Valencia, Craig Weiss, Laura A Dada, Edward B Thorp, Jacob I Sznajder, Navdeep S Chandel, Alexander V Misharin, G R Scott Budinger.
      Sarcopenia, which diminishes lifespan and healthspan in the elderly, is commonly exacerbated by viral pneumonia, including influenza and COVID-19. In a study of influenza A pneumonia in mice, young mice fully recovered from sarcopenia, while older mice did not. We identified a population of tissue-resident skeletal muscle macrophages that form a spatial niche with satellite cells and myofibers in young mice but are lost with age. Mice with a gain-of-function mutation in the Mertk receptor maintained this macrophage-myofiber interaction during aging and fully recovered from influenza-induced sarcopenia. In contrast, deletion of Mertk in macrophages or loss of Cx3cr1 disrupted this niche, preventing muscle regeneration. Heterochronic parabiosis did not restore the niche in old mice. These findings suggest that age-related loss of Mertk in muscle tissue-resident macrophages disrupts the cellular signaling necessary for muscle regeneration after viral pneumonia, offering a potential target to mitigate sarcopenia in aging.
    DOI:  https://doi.org/10.1101/2025.01.09.631996
  12. Medicina (Kaunas). 2025 Jan 09. pii: 96. [Epub ahead of print]61(1):
    Mitochondrial Ribosomal Proteins and Cancer.
    Huiyi Wu, Xiaowei Zhu, Huilin Zhou, Min Sha, Jun Ye, Hong Yu.
      Mitochondria play key roles in maintaining cell life and cell function, and their dysfunction can lead to cell damage. Mitochondrial ribosomal proteins (MRPs) are encoded by nuclear genes and are assembled within the mitochondria. MRPs are pivotal components of the mitochondrial ribosomes, which are responsible for translating 13 mitochondrial DNA-encoded proteins essential for the mitochondrial respiratory chain. Recent studies have underscored the importance of MRPs in cancer biology, revealing their altered expression patterns in various types of cancer and their potential as both prognostic biomarkers and therapeutic targets. Herein, we review the current knowledge regarding the multiple functions of MRPs in maintaining the structure of the mitochondrial ribosome and apoptosis, their implications for cancer susceptibility and progression, and the innovative strategies being developed to target MRPs and mitoribosome biogenesis in cancer therapy. This comprehensive overview aims to provide insights into the role of MRPs in cancer biology and highlight promising strategies for future precision oncology.
    Keywords:  apoptosis; biomarker; mitochondrial dysfunction; mitoribosome; precision oncology
    DOI:  https://doi.org/10.3390/medicina61010096
  13. J Dent Sci. 2025 Jan;20(1): 613-619
    Sodium butyrate activates the extrinsic and intrinsic apoptotic processes in murine cementoblasts.
    Shih-Kai Lo, Ni-Yu Su, Chun-Chuan Su, Yu-Chao Chang.
       Background: /purpose: The metabolic by-product butyric acid of Gram-negative anaerobic bacteria can invoke pathological effects on periodontal cells resulting in inflammation and further destruction of periodontium. However, limited researches on the effects of butyric acid on cementoblasts were reported. Therefore, this study aimed to investigate the type of cell death in murine cementoblast (OCCM.30) caused by adding the different concentrations of sodium butyrate to the cell culture.
    Materials and methods: OCCM.30 cells were exposed to sodium butyrate (0, 2, 4, 8, 16 mM) for 48 h. Cell viability was determined by microculture tetrazolium assay. Cell cycle distribution and cell death were analyzed by flow cytometry. Caspase-mediated apoptotic cascade was evaluated by Western blot.
    Results: The concentrations of sodium butyrate≧4 mM were found to inhibit cell viability of OCCM.30 cells in a dose-dependent manner (P < 0.05). Sodium butyrate elevated sub-G1 cell population which exhibited cell apoptosis in OCCM.30 cells (P < 0.05). In addition, early and later apoptotic cells were found in sodium butyrate-induced cell death. Sodium butyrate significantly stimulated the degradation of procaspases-3, -8, and -9 levels, respectively (P < 0.05). Simultaneously, sodium butyrate corresponded to augment the levels of cleaved forms of caspases-3, -8, and -9, respectively (P < 0.05).
    Conclusion: Taken together, sodium butyrate is a cytotoxic agent and can induce apoptosis on cementoblasts. The pathway involved in apoptosis is activated by caspase family signaling pathways. These evidences may provide a new mechanistic insight into the mechanism of damage of cementoblasts during the development and progression of periodontitis.
    Keywords:  Apoptosis; Cementoblast; Periodontitis; Short-chain fatty acids; Sodium butyrate
    DOI:  https://doi.org/10.1016/j.jds.2024.11.006
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