bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2025–03–30
twenty-two papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello
  1. Metabolic and Pharmacokinetic Profiling of a Ketone Ester by Background SGLT2 Inhibitor Therapy in HFrEF.
  2. Changes in plasma cytokines following a 60-h fast are not influenced by the addition of exercise despite elevated ketones in healthy young adults.
  3. Nutritional ketosis modulates the methylation of cancer-related genes in patients with obesity and in breast cancer cells.
  4. Fasting for weight loss is all the rage: what are the health benefits?
  5. Ketogenic diet, adenosine, and dopamine in addiction and psychiatry.
  6. Have Your Sodium-Glucose Cotransporter 2 Inhibitor-Derived Ketones and Eat Them Too.
  7. Biological sex does not impact intrinsic mitochondrial respiration supported by complexes I and II in human skeletal muscle.
  8. A map of mitochondrial biology reveals the energy landscape of the human brain.
  9. Mechanistic insights into impaired β-oxidation and its role in mitochondrial dysfunction: A comprehensive review.
  10. In situ architecture of the human prohibitin complex.
  11. First map of human brain mitochondria is 'groundbreaking' achievement.
  12. A human brain map of mitochondrial respiratory capacity and diversity.
  13. Endurance exercise with reduced muscle glycogen content influences substrate utilization and attenuates acute mTORC1- and autophagic signaling in human type I and type II muscle fibers.
  14. A New Perspective on the Role of Alterations in Mitochondrial Proteins Involved in ATP Synthesis and Mobilization in Cardiomyopathies.
  15. Time-restricted eating in people at high diabetes risk does not affect mitochondrial bioenergetics in peripheral blood mononuclear cells and platelets.
  16. Sodium butyrate alleviates spinal cord injury via inhibition of NLRP3/Caspase-1/GSDMD-mediated pyroptosis.
  17. Loss of Skeletal Muscle Inositol Polyphosphate Multikinase Disrupts Glucose Regulation and Limits Exercise Capacity.
  18. The fate of mitochondrial respiratory complexes in aging.
  19. Physical training reduces cell senescence and associated insulin resistance in skeletal muscle.
  20. Cell biology: A new dynamin superfamily protein remodels mitochondrial dynamics.
  21. MAM kinases: physiological roles, related diseases, and therapeutic perspectives-a systematic review.
  22. Exercise Delays Brain Ageing Through Muscle-Brain Crosstalk.
  1. JACC Basic Transl Sci. 2025 Mar;pii: S2452-302X(24)00393-0. [Epub ahead of print]10(3): 290-303
    Metabolic and Pharmacokinetic Profiling of a Ketone Ester by Background SGLT2 Inhibitor Therapy in HFrEF.
    Senthil Selvaraj, Lydia Coulter Kwee, Elizabeth J Thompson, Mengshu He, Christoph P Hornik, Adam D Devore, Chetan B Patel, Robert J Mentz, Marat Fudim, Lacey Taylor, Stephanie Milosovic, Melissa Hurdle, William T Cade, Olga Ilkayeva, Michael J Muehlbauer, Christopher B Newgard, Daniel P Kelly, Payman Zamani, Kenneth B Margulies, Svati H Shah.
      Growing evidence supports therapeutic ketosis in heart failure with reduced ejection fraction, though uncertainty exists regarding use with SGLT2i and dose-dependent effects. In a phase I trial of 2 ketone ester (KE) doses in 20 heart failure with reduced ejection fraction participants, stratified by background SGLT2i, the authors detailed pharmacokinetic parameters, noting rapid ketosis and short half-life. KE was associated with lower non-esterified fatty acid, branched-chain amino acids, and most acylcarnitines (except C2 and C4-OH, which increased); differences were observed by SGLT2i and KE dose. Increases in heart rate and decreases in systolic blood pressure, pH, and bicarbonate were generally transient. KE ingestion induces rapid changes in key metabolic pathways, differentially affected by SGLT2i (fatty acid metabolism) and KE dose (ketone metabolism). Hemodynamic effects were transient and irrespective of dose or SGLT2i. (Ketone Pharmacokinetic Study in HFrEF; NCT05757193).
    Keywords:  SGLT2 inhibitor; acylcarnitine; heart failure with reduced ejection fraction; insulin; ketone bodies; metabolomics
    DOI:  https://doi.org/10.1016/j.jacbts.2024.10.014
  2. Physiol Rep. 2025 Mar;13(6): e70294
    Changes in plasma cytokines following a 60-h fast are not influenced by the addition of exercise despite elevated ketones in healthy young adults.
    Tori Bouck, Justin Monteleone, Jennifer Duffy, Philip N Ainslie, Jonathan P Little, Kate N Thomas, Travis D Gibbons, Hashim Islam.
      Immunometabolic processes maintain physiological homeostasis and are implicated in various chronic diseases. Fasting and exercise independently alter metabolic and immunological processes; their combination could provide insights into immunometabolic interactions. Using a randomized crossover design, 15 healthy adults (six females, nine males, 26.5 ± 4.3 years) fasted for 60 h with and without the addition of a 3 h cycling bout (65%-80% VO2 peak). Fasting alone (FAST) and with exercise (FEX) reduced plasma glucose, insulin, respiratory exchange ratio, and increased β-hydroxybutyrate (BHB; all p < 0.01). FEX elicited more rapid changes in glucose and BHB and higher BHB concentrations at 60 h (all p < 0.01). Both conditions decreased circulating TNF-⍺ concentrations and increased IL-10 (p < 0.01), although the increase in IL-10 appeared to be driven by the FEX condition (p = 0.03). IL-6 concentrations tended to increase in both conditions (p = 0.1). Total white blood cell count remained unchanged after 60 h in both conditions, with only modest changes in some leukocyte subpopulations. Collectively, the observed changes in circulating cytokine concentrations support an overall anti-inflammatory effect of prolonged fasting, while the maintenance of leukocyte concentrations suggests immune function is not compromised. Despite greater metabolic strain, the addition of prolonged exercise did not appear to augment changes in systemic cytokines and leukocytes.
    Keywords:  immunometabolism; inflammation; interleukin‐10; interleukin‐6; leukocytes; tumor necrosis factor‐alpha
    DOI:  https://doi.org/10.14814/phy2.70294
  3. J Physiol Biochem. 2025 Mar 27.
    Nutritional ketosis modulates the methylation of cancer-related genes in patients with obesity and in breast cancer cells.
    Paula M Lorenzo, Andrea G Izquierdo, Gemma Rodriguez-Carnero, Nicolas Costa-Fraga, Angel Díaz-Lagares, Cristina Porca, Daniel de Luis, Cristina Tejera, Laura De Paz, Juan Cueva, Diego Bellido, Ana B Crujeiras.
      Scientific evidence demonstrates that a very low-calorie ketogenic diet (VLCKD) is effective and beneficial in the treatment of obesity, capable of reversing the methylome associated with obesity and has immunomodulatory capacity. This effect is in part promoted by nutritional ketosis and could be involved in counteracting obesity-related cancer. The aim of this study was to evaluate the effect of nutritional ketosis on the methylation of genes related to tumor processes in patients with obesity and in breast cancer cells. Based on methylome data (Infinium MethylationEPIC BeadChip, Illumina) from patients with obesity treated with a VLCKD for weight loss (n = 10; n = 5 women, age = 48.8 ± 9.20 years, BMI = 32.9 ± 1.4 kg/m2), genes belonging to cancer-related pathways were specifically evaluated and further validated in vitro in MDA-MB-231 (triple negative) and MCF7 (RE positive) breast tumor cells pretreated for 72 h with βOHB, the main ketone body, secretome from visceral (VATs) or subcutaneous (SATs) adipose tissue of patients with obesity. The cell tumoral phenotype was evaluated by proliferation assay and expression of cancer-related genes. VLCKD-induced nutritional ketosis promoted changes in the methylation of 18 genes (20 CpGs; 17 hypomethylated, 3 hypermethylated) belonged to cancer-related pathways with MAPK10, CCN1, CTNNA2, LAMC3 and GLI2 being the most representative genes. A similar pattern was observed in the MDA-MB-231 cells treated with β-OHB, without changes in MCF7. These epigenetic changes paralleled the tumoral phenotype modulated by the treatments. Taking together these results highlight the potential role of VLCKD as an adjuvant to anticancer treatment in groups more susceptible to the development of cancer such as patients with obesity, exerting epigenetic regulation through nutritional ketosis and weight loss.
    Keywords:  Adipose tissue; Breast cancer; DNMTs; Epigenetics; Ketogenic diet; Ketone bodies; Oncogenes; Sirtuins; Tumor suppressors
    DOI:  https://doi.org/10.1007/s13105-025-01076-9
  4. Nature. 2025 Mar;639(8056): 855-857
    Fasting for weight loss is all the rage: what are the health benefits?
    Nic Fleming.
      
    Keywords:  Ageing; Nutrition; Obesity
    DOI:  https://doi.org/10.1038/d41586-025-00895-6
  5. Front Nutr. 2025 ;12 1492306
    Ketogenic diet, adenosine, and dopamine in addiction and psychiatry.
    David N Ruskin, Luis A Martinez, Susan A Masino.
      Adhering to the ketogenic diet can reduce or stop seizures, even when other treatments fail, via mechanism(s) distinct from other available therapies. These results have led to interest in the diet for treating conditions such as Alzheimer's disease, depression and schizophrenia. Evidence points to the neuromodulator adenosine as a key mechanism underlying therapeutic benefits of a ketogenic diet. Adenosine represents a unique and direct link among cell energy, neuronal activity, and gene expression, and adenosine receptors form functional heteromers with dopamine receptors. The importance of the dopaminergic system is established in addiction, as are the challenges of modulating the dopamine system directly. A mediator that could antagonize dopamine's effects would be useful, and adenosine is such a mediator due to its function and location. Studies report that the ketogenic diet improves cognition, sociability, and perseverative behaviors, and might improve depression. Many of the translational opportunities based on the ketogenic diet/adenosine link have come to the fore, including addiction, autism spectrum disorder, painful conditions, and a range of hyperdopaminergic disorders.
    Keywords:  addiction; adenosine; dopamine; ketogenic diet; mental health; metabolic psychiatry; psychiatric disorder
    DOI:  https://doi.org/10.3389/fnut.2025.1492306
  6. JACC Basic Transl Sci. 2025 Mar;pii: S2452-302X(24)00488-1. [Epub ahead of print]10(3): 304-306
    Have Your Sodium-Glucose Cotransporter 2 Inhibitor-Derived Ketones and Eat Them Too.
    Virginia S Hahn, Navid Koleini.
      
    Keywords:  heart failure; ketones; metabolomics; sodium glucose cotransporter 2 inhibitors
    DOI:  https://doi.org/10.1016/j.jacbts.2024.12.013
  7. Exp Physiol. 2025 Mar 26.
    Biological sex does not impact intrinsic mitochondrial respiration supported by complexes I and II in human skeletal muscle.
    Emily J Ferguson, Lauren J Pacitti, Justin Bureau, Callum J Pufahl, Eveline Menezes, Tanner Stokes, Shivam Gandhi, Luca J Delfinis, Craig A Simpson, Christopher G R Perry, Brendon J Gurd, Chris McGlory.
      The effect of biological sex on rates of skeletal muscle mitochondrial respiration supported by creatine-dependent phosphate shuttling was previously unknown. The aim of this investigation was to test the hypothesis that females and males matched for peak oxygen uptake normalized to fat-free mass would not exhibit differences in rates of mass-specific and intrinsic mitochondrial respiration in the presence or absence of creatine. Rates of mass-specific and intrinsic complex I (pyruvate and malate)- and complex I+II-supported, adenosine diphosphate (ADP)-stimulated mitochondrial respiration in the presence and absence of 20 mM creatine were measured via high-resolution respirometry. Total, intermyofibrillar and subsarcolemmal mitochondrial volume density were analysed using transmission electron microscopy. Rates of intrinsic mitochondrial respiration were obtained by normalizing mass-specific respiration rates to total mitochondrial volume density and total electron transport chain subunit protein content. Overall, there was no effect of sex on rates of mass-specific or intrinsic mitochondrial respiration in the presence or absence of creatine. There was also no effect of sex on total, intermyofibrillar and subsarcolemmal mitochondrial volume density or electron transport chain subunit protein content. Our data demonstrate an overall lack of sex-based differences in rates of intrinsic complex I- and complex I+II-supported, ADP-stimulated mitochondrial respiration in the presence or absence of creatine in females and males matched for aerobic fitness. Thus, biological sex per se does not appear to modulate intrinsic skeletal muscle mitochondrial respiration in healthy young adults.
    Keywords:  aerobic fitness; biological sex; creatine; human skeletal muscle; intrinsic mitochondrial respiration; mitochondrial content
    DOI:  https://doi.org/10.1113/EP092551
  8. Nature. 2025 Mar 26.
    A map of mitochondrial biology reveals the energy landscape of the human brain.
      
    Keywords:  Brain; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-00872-z
  9. Diabetes Res Clin Pract. 2025 Mar 23. pii: S0168-8227(25)00143-3. [Epub ahead of print] 112129
    Mechanistic insights into impaired β-oxidation and its role in mitochondrial dysfunction: A comprehensive review.
    Amna Aqeel, Areeba Akram, Minahil Ali, Maryam Iqbal, Mehral Aslam, Rukhma Sattar, Fatima Iftikhar Shah.
      Mitochondria, also known as the powerhouse of cells, have an important role in cellular metabolism and energy production. However, during Mitochondrial Dysfunction (MD), it is known to generate reactive oxidative species and induce cellular apoptosis. A number of research findings have linked MD to various diseases, highlighting its critical role in maintaining health and contributing to disease development. In this regard, recent research has revealed that disruptions in lipid metabolism, especially in fatty acid oxidation, are significant contributors to MD. However, the precise mechanisms by which these defects lead to disease remain poorly understood. This review explores how disruptions in lipid metabolism are responsible for triggering oxidative stress, inflammation, and cellular damage, leading to impaired mitochondrial function. By examining specific fatty acid oxidation disorders, such as carnitine palmitoyltransferase deficiency, medium-chain acyl-CoA dehydrogenase deficiency, and very long-chain acyl-CoA dehydrogenase deficiency, this review aims to uncover the underlying molecular pathways connecting lipid metabolism to mitochondrial dysfunction. Furthermore, MD is a common underlying mechanism in a wide array of diseases, including neurodegenerative disorders, and metabolic syndromes. Understanding the mechanisms behind mitochondrial malfunction may aid in the development of tailored therapies to restore mitochondrial health and treat intricate health conditions.
    Keywords:  Fatty acid oxidation disorders (FAODs); Lipid metabolism; Mitochondrial dysfunction; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.diabres.2025.112129
  10. Nat Cell Biol. 2025 Mar 21.
    In situ architecture of the human prohibitin complex.
    Felix Lange, Michael Ratz, Jan-Niklas Dohrke, Maxence Le Vasseur, Dirk Wenzel, Peter Ilgen, Dietmar Riedel, Stefan Jakobs.
      Prohibitins are a highly conserved family of proteins that have been implicated in a variety of functions including mitochondrial stress signalling and housekeeping, cell cycle progression, apoptosis, lifespan regulation and many others. The human prohibitins prohibitin 1 and prohibitin 2 have been proposed to act as scaffolds within the mitochondrial inner membrane, but their molecular organization has remained elusive. Here we determined the molecular organization of the human prohibitin complex within the mitochondrial inner membrane using an integrative structural biology approach combining quantitative western blotting, cryo-electron tomography, subtomogram averaging and molecular modelling. The proposed bell-shaped structure consists of 11 alternating prohibitin 1 and prohibitin 2 molecules. This study reveals an average of about 43 prohibitin complexes per crista, covering 1-3% of the crista membrane area. These findings provide a structural basis for understanding the functional contributions of prohibitins to the integrity and spatial organization of the mitochondrial inner membrane.
    DOI:  https://doi.org/10.1038/s41556-025-01620-1
  11. Nature. 2025 Mar 26.
    First map of human brain mitochondria is 'groundbreaking' achievement.
    Nora Bradford.
      
    Keywords:  Brain; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-00848-z
  12. Nature. 2025 Mar 26.
    A human brain map of mitochondrial respiratory capacity and diversity.
    Eugene V Mosharov, Ayelet M Rosenberg, Anna S Monzel, Corey A Osto, Linsey Stiles, Gorazd B Rosoklija, Andrew J Dwork, Snehal Bindra, Alex Junker, Ya Zhang, Masashi Fujita, Madeline B Mariani, Mihran Bakalian, David Sulzer, Philip L De Jager, Vilas Menon, Orian S Shirihai, J John Mann, Mark D Underwood, Maura Boldrini, Michel Thiebaut de Schotten, Martin Picard.
      Mitochondrial oxidative phosphorylation (OXPHOS) powers brain activity1,2, and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders3,4. To understand the basis of brain activity and behaviour, there is a need to define the molecular energetic landscape of the brain5-10. Here, to bridge the scale gap between cognitive neuroscience and cell biology, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3 × 3 × 3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes, including OXPHOS enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains diverse mitochondrial phenotypes driven by both topology and cell types. Compared with white matter, grey matter contains >50% more mitochondria. Moreover, the mitochondria in grey matter are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backwards linear regression model that integrates several neuroimaging modalities11 to generate a brain-wide map of mitochondrial distribution and specialization. This model predicted mitochondrial characteristics in an independent brain region of the same donor brain. This approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain function. This resource also relates to neuroimaging data and defines the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders. All data are available at http://humanmitobrainmap.bcblab.com .
    DOI:  https://doi.org/10.1038/s41586-025-08740-6
  13. Skelet Muscle. 2025 Mar 25. 15(1): 9
    Endurance exercise with reduced muscle glycogen content influences substrate utilization and attenuates acute mTORC1- and autophagic signaling in human type I and type II muscle fibers.
    Oscar Horwath, Lucas Cornet, Henrik Strömlind, Marcus Moberg, Sebastian Edman, Karin Söderlund, Antonio Checa, Jorge L Ruas, Eva Blomstrand.
       BACKGROUND: Exercising with low muscle glycogen content can improve training adaptation, but the mechanisms underlying the muscular adaptation are still largely unknown. In this study, we measured substrate utilization and cell signaling in different muscle fiber types during exercise and investigated a possible link between these variables.
    METHODS: Five subjects performed a single leg cycling exercise in the evening (day 1) with the purpose of reducing glycogen stores. The following morning (day 2), they performed two-legged cycling at ∼70% of VO2peak for 1 h. Muscle biopsies were taken from both legs pre- and post-exercise for enzymatic analyses of glycogen, metabolite concentrations using LC-MS/MS-based quantification, and protein signaling using Western blot in pools of type I or type II fibers.
    RESULTS: Glycogen content was 60-65% lower for both fiber types (P < 0.01) in the leg that exercised on day 1 (low leg) compared to the other leg with normal level of glycogen (normal leg) before the cycling exercise on day 2. Glycogen utilization during exercise was significantly less in both fiber types in the low compared to the normal leg (P < 0.05). In the low leg, there was a 14- and 6-fold increase in long-chain fatty acids conjugated to carnitine in type I and type II fibers, respectively, post-exercise. This increase was 3-4 times larger than in the normal leg (P < 0.05). Post-exercise, mTORSer2448 phosphorylation was increased in both fiber types in the normal leg (P < 0.05) but remained unchanged in both fiber types in the low leg together with an increase in eEF2Thr56 phosphorylation in type I fibers (P < 0.01). Exercise induced a reduction in the autophagy marker LC3B-II in both fiber types and legs, but the post-exercise level was higher in both fiber types in the low leg (P < 0.05). Accordingly, the LC3B-II/I ratio decreased only in the normal leg (75% for type I and 87% for type II, P < 0.01).
    CONCLUSIONS: Starting an endurance exercise session with low glycogen availability leads to profound changes in substrate utilization in both type I and type II fibers. This may reduce the mTORC1 signaling response, primarily in type I muscle fibers, and attenuate the normally observed reduction in autophagy.
    Keywords:  Autophagy; Fatty acids; Metabolomics; Muscle fiber type; mTORC1
    DOI:  https://doi.org/10.1186/s13395-025-00377-3
  14. Int J Mol Sci. 2025 Mar 19. pii: 2768. [Epub ahead of print]26(6):
    A New Perspective on the Role of Alterations in Mitochondrial Proteins Involved in ATP Synthesis and Mobilization in Cardiomyopathies.
    Melissa Vázquez-Carrada, María Magdalena Vilchis-Landeros, Héctor Vázquez-Meza, Daniel Uribe-Ramírez, Deyamira Matuz-Mares.
      The heart requires a continuous energy supply to sustain its unceasing contraction-relaxation cycle. Mitochondria, a double-membrane organelle, generate approximately 90% of cellular energy as adenosine triphosphate (ATP) through oxidative phosphorylation, utilizing the electrochemical gradient established by the respiratory chain. Mitochondrial function is compromised by damage to mitochondrial DNA, including point mutations, deletions, duplications, or inversions. Additionally, disruptions to proteins associated with mitochondrial membranes regulating metabolic homeostasis can impair the respiratory chain's efficiency. This results in diminished ATP production and increased generation of reactive oxygen species. This review provides an overview of mutations affecting mitochondrial transporters and proteins involved in mitochondrial energy synthesis, particularly those involved in ATP synthesis and mobilization, and it examines their role in the pathogenesis of specific cardiomyopathies.
    Keywords:  ATP synthesis; cardiomyopathies; mitochondria; mitochondrial DNA; point mutations
    DOI:  https://doi.org/10.3390/ijms26062768
  15. Sci Rep. 2025 Mar 24. 15(1): 10175
    Time-restricted eating in people at high diabetes risk does not affect mitochondrial bioenergetics in peripheral blood mononuclear cells and platelets.
    Joana Mendes Lopes de Melo, Martin Bæk Blond, Verena Hirschberg Jensen, Hanne Pedersen, Kim Katrine Bjerring Clemmensen, Marie Møller Jensen, Kristine Færch, Jonas Salling Quist, Joachim Størling.
      Overweight and obesity are linked to mitochondrial alterations, impaired glucose tolerance and a high risk of type 2 diabetes. Time-restricted eating (TRE) may aid in facilitating weight loss to prevent diabetes. Here, we investigated if TRE in individuals with overweight and prediabetes or obesity affects mitochondrial bioenergetics of peripheral blood mononuclear cells (PBMCs) and platelets using the Seahorse extracellular flux technology. In a 3-month randomized controlled trial, PBMCs/platelets were analyzed from 52 participants before and after a TRE intervention with a 10-h eating window or habitual living. PBMC and platelet respiratory function was evaluated through sequential addition of substrates, uncouplers, and inhibitors in living cells. After 3 months, there were no statistically significant differences in mitochondrial respiration within or between the TRE and control groups. Association analyses between PBMC/platelet respiration and clinical parameters including body mass index and fat mass showed no significant effects. In conclusion, 3 months of 10-h TRE does not alter the mitochondrial bioenergetics of PBMCs and platelets in individuals with high risk of type 2 diabetes.
    Keywords:  Bioenergetics; Mitochondria; Obesity; Overweight; Oxidative phosphorylation; Oxygen consumption rate (OCR); Peripheral blood mononuclear cells (PBMCs); Platelets; Pre-diabetes; Seahorse extracellular flux; Time-restricted eating (TRE); Type 2 diabetes (T2D)
    DOI:  https://doi.org/10.1038/s41598-025-94652-4
  16. Metab Brain Dis. 2025 Mar 24. 40(4): 157
    Sodium butyrate alleviates spinal cord injury via inhibition of NLRP3/Caspase-1/GSDMD-mediated pyroptosis.
    Yanru Cui, Qiuyu Cen, Jing Feng, Juanfang Wei, Linjie Wang, Cong Chang, Rizhao Pang, Junyu Wang, Anren Zhang.
      NOD-like receptor protein 3 (NLRP3)/cysteinyl aspartate-specific proteinase 1 (Caspase-1)/gasdermin D (GSDMD)-mediated pyroptosis is linked to spinal cord injury (SCI) pathogenesis. The levels of short-chain fatty acids (SCFAs), especially butyric acid, are significantly altered after SCI. Sodium butyrate (NaB) has anti-inflammatory effects on SCI; however, its effect on pyroptosis is unknown. The aim of this study was to determine the role of NaB in SCI functional recovery and its effect on NLRP3/Caspase-1/GSDMD-mediated pyroptosis. SCI model rats were established using aneurysm clips. After SCI, rats were administered NaB (300 mg/kg) via gavage. SCFAs in faeces were measured using gas chromatography-mass spectrometry. Motor function recovery was assessed using cylinder rearing and grooming tests. Histopathological analysis was performed using haematoxylin-eosin staining, transmission electron microscopy, and terminal deoxynucleotidyl transferase dUTP nick-end labelling. The expression of proteins associated with pyroptosis signalling pathways was analysed using enzyme-linked immunosorbent assay, western blotting, and immunohistochemistry. SCFAs levels, particularly butyric acid, significantly decreased after SCI. NaB treatment promoted forelimb motor function recovery and attenuated pathological SCI. NaB also decreased spinal pro-inflammatory factors (interleukin-18 and interleukin-1β) and downregulated pyroptosis-related proteins, including NLRP3, apoptosis-associated speck-like protein, Caspase-1, and GSDMD. NaB inhibits NLRP3/Caspase-1/GSDMD-mediated neuronal pyroptosis and inflammation, exerting protective and therapeutic effects in SCI, suggesting NaB as an effective SCI treatment.
    Keywords:  Neuroinflammation; Pyroptosis; Sodium butyrate; Spinal cord injury
    DOI:  https://doi.org/10.1007/s11011-025-01589-8
  17. Int J Mol Sci. 2025 Mar 07. pii: 2395. [Epub ahead of print]26(6):
    Loss of Skeletal Muscle Inositol Polyphosphate Multikinase Disrupts Glucose Regulation and Limits Exercise Capacity.
    Ji-Hyun Lee, Ik-Rak Jung, Becky Tu-Sekine, Sunghee Jin, Frederick Anokye-Danso, Rexford S Ahima, Sangwon F Kim.
      Inositol phosphates are critical signaling messengers involved in a wide range of biological pathways, and inositol polyphosphate multikinase (IPMK) functions as a rate-limiting enzyme for inositol polyphosphate metabolism. IPMK has been implicated in cellular metabolism, but its function at the systemic level is still poorly understood. Since skeletal muscle is a major contributor to energy homeostasis, we have developed a mouse model in which skeletal muscle IPMK is specifically deleted and examined how a loss of IPMK affects whole-body metabolism. Here, we report that skeletal-muscle-specific IPMK knockout mice exhibited a ~12% increase in body weight compared to WT controls (p < 0.05). These mice also showed a significantly impaired glucose tolerance, as indicated by their ~50% higher blood glucose levels during GTT. Additionally, exercise capacity was reduced by ~45% in IPMK-MKO mice, demonstrating a decline in endurance. Moreover, these metabolic alterations were accompanied by a 2.5-fold increase in skeletal muscle triglyceride accumulation, suggesting impaired lipid metabolism. Further analysis revealed that IPMK-deficient myocytes exhibited 30% lower β-oxidation rates. Thus, our results suggest that IPMK mediates whole-body metabolism by regulating muscle metabolism and may be potentially targeted for the treatment of metabolic syndromes.
    Keywords:  IPMK; exercise; inositol polyphosphate; insulin; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms26062395
  18. Trends Cell Biol. 2025 Mar 26. pii: S0962-8924(25)00042-X. [Epub ahead of print]
    The fate of mitochondrial respiratory complexes in aging.
    Hanna Salmonowicz, Karolina Szczepanowska.
      While mitochondrial dysfunction is one of the canonical hallmarks of aging, it remains only vaguely defined. Its core feature embraces defects in energy-producing molecular machinery, the mitochondrial respiratory complexes (MRCs). The causes and consequences of these defects hold research attention. In this review, we assess the lifecycle of respiratory complexes, from biogenesis to degradation, and look closely at the mechanisms that could underpin their dysfunction in aged cells. We discuss how these processes could be altered by aging and expand on the fate of MRCs in age-associated pathologies. Given the complexity behind MRC maintenance and functionality, several traits could contribute to the phenomenon known as age-associated mitochondrial dysfunction. New advances will help us better understand the fate of this machinery in aging and age-related diseases.
    Keywords:  OXPHOS; age-associated diseases; dysfunction; mitochondria; protein complexes, aging hallmarks
    DOI:  https://doi.org/10.1016/j.tcb.2025.02.008
  19. Mol Metab. 2025 Mar 22. pii: S2212-8778(25)00037-7. [Epub ahead of print] 102130
    Physical training reduces cell senescence and associated insulin resistance in skeletal muscle.
    Agnieszka Podraza-Farhanieh, Rosa Spinelli, Federica Zatterale, Annika Nerstedt, Silvia Gogg, Matthias Blüher, Ulf Smith.
       BACKGROUND: Cellular senescence (CS) is a key aging process that leads to irreversible cell cycle arrest and an altered secretory phenotype. In skeletal muscle (SkM), the accumulation of senescent cells contributes to sarcopenia. Despite exercise being a known intervention for maintaining SkM function and metabolic health, its effects on CS remain poorly understood.
    OBJECTIVES: This study aimed to investigate the impact of exercise on CS in human SkM by analyzing muscle biopsies from young, normal-weight individuals and middle-aged individuals with obesity, both before and after exercise intervention.
    METHODS: Muscle biopsies were collected from both groups before and after an exercise intervention. CS markers, insulin sensitivity (measured with euglycemic clamp), and satellite cell markers were analyzed. Additionally, in vitro experiments were conducted to evaluate the effects of cellular senescence on human satellite cells, focusing on key regulatory genes and insulin signaling.
    RESULTS: Individuals with obesity showed significantly elevated CS markers, along with reduced expression of GLUT4 and PAX7, indicating impaired insulin action and regenerative potential. Exercise improved insulin sensitivity, reduced CS markers, and activated satellite cell response in both groups. In vitro experiments revealed that senescence downregulated key regulatory genes in satellite cells and impaired insulin signaling by reducing the Insulin Receptor β-subunit.
    CONCLUSIONS: These findings highlight the role of CS in regulating insulin sensitivity in SkM and underscore the therapeutic potential of exercise in mitigating age- and obesity-related muscle dysfunction. Targeting CS through exercise or senolytic agents could offer a promising strategy for improving metabolic health and combating sarcopenia, particularly in at-risk populations.
    Keywords:  Aging; Cellular senescence; Exercise intervention; Obesity; Satellite cells; Skeletal muscles
    DOI:  https://doi.org/10.1016/j.molmet.2025.102130
  20. Curr Biol. 2025 Mar 24. pii: S0960-9822(25)00132-0. [Epub ahead of print]35(6): R218-R221
    Cell biology: A new dynamin superfamily protein remodels mitochondrial dynamics.
    Hassan Hashimi.
      Dynamin superfamily proteins mediate mitochondrial fusion in fungi and animals. A new study expands the taxonomic reach of this superfamily and provides insights into the roles these proteins play by investigating MfnL, a family member involved in trypanosomal mitochondrial dynamics. Importantly, MfnL occurs widely in eukaryotes and prokaryotes.
    DOI:  https://doi.org/10.1016/j.cub.2025.01.069
  21. Cell Mol Biol Lett. 2025 Mar 28. 30(1): 35
    MAM kinases: physiological roles, related diseases, and therapeutic perspectives-a systematic review.
    A Anjana Mohan, Priti Talwar.
      Mitochondria-associated membranes (MAMs) are tethering regions amid the membranes of the endoplasmic reticulum (ER) and mitochondria. They are a lipid raft-like structure occupied by various proteins that facilitates signal transduction between the two organelles. The MAM proteome participates in cellular functions such as calcium (Ca2+) homeostasis, lipid synthesis, ER stress, inflammation, autophagy, mitophagy, and apoptosis. The human kinome is a superfamily of homologous proteins consisting of 538 kinases. MAM-associated kinases participate in the aforementioned cellular functions and act as cell fate executors. Studies have proved the dysregulated kinase interactions in MAM as an etiology for various diseases including cancer, diabetes mellitus, neurodegenerative diseases, cardiovascular diseases (CVDs), and obesity. Several small kinase inhibitory molecules have been well explored as promising drug candidates in clinical trials with an accelerating impact in the field of precision medicine. This review narrates the physiological actions, pathophysiology, and therapeutic potential of MAM-associated kinases with recent updates in the field.
    Keywords:  Cancer; Diabetes; ER stress; Kinases; MAM; Mitophagy; Neurodegenerative disease; Therapeutics
    DOI:  https://doi.org/10.1186/s11658-025-00714-w
  22. Cell Prolif. 2025 Mar 24. e70026
    Exercise Delays Brain Ageing Through Muscle-Brain Crosstalk.
    Shirin Pourteymour, Rakesh Kumar Majhi, Frode A Norheim, Christian A Drevon.
      Ageing is often accompanied by cognitive decline and an increased risk of dementia. Exercise is a powerful tool for slowing brain ageing and enhancing cognitive function, as well as alleviating depression, improving sleep, and promoting overall well-being. The connection between exercise and healthy brain ageing is particularly intriguing, with exercise-induced pathways playing key roles. This review explores the link between exercise and brain health, focusing on how skeletal muscle influences the brain through muscle-brain crosstalk. We examine the interaction between the brain with well-known myokines, including brain-derived neurotrophic factor, macrophage colony-stimulating factor, vascular endothelial growth factor and cathepsin B. Neuroinflammation accumulates in the ageing brain and leads to cognitive decline, impaired motor skills and increased susceptibility to neurodegenerative diseases. Finally, we examine the evidence on the effects of exercise on neuronal myelination in the central nervous system, a crucial factor in maintaining brain health throughout the lifespan.
    Keywords:  CNS myelination; brain; brain ageing; exercise; healthy ageing; myokines and brain health
    DOI:  https://doi.org/10.1111/cpr.70026
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