bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2025–04–27
thirteen papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello



  1. Gut Microbes. 2025 Dec;17(1): 2496437
      The ketogenic diet (KD) induces prolonged hyperketonemia, characterized by elevated circulating level of β-hydroxybutyrate. However, the KD can negatively affect host metabolic health by altering the gut microbial community. Despite this, the regulatory effect of the gut microbiota on hepatic ketogenesis and triacylglycerol (TAG) accumulation during a KD remains poorly understood. Here, we hypothesized that the commensal bacterium regulates hepatic lipid metabolism in association with KD-induced hyperketonemia. The KD disrupts the remodeling of the gut microbiota following antibiotic-induced depletion. The capacity for ketogenesis and the severity of TAG accumulation in the liver closely correlated with changes in the gut microbial composition and the up-regulation of hepatic farnesoid X receptor (FXR), peroxisome proliferator-activated receptor alpha (PPARα), and diacylglycerol O-acyltransferase 2 (DGAT2), which were modulated by bile acid metabolism through the gut-liver axis. The commensal bacterium Clostridium perfringens type A is particularly implicated in prolonged hyperketonemia, exacerbating hepatic ketogenesis and steatosis by disrupting secondary bile acid metabolism. The increased conversion of deoxycholic acid to 12-ketolithocholic acid represents a critical microbial pathway during C. perfringens colonization. These findings illuminate the adverse effects of the gut microbiota on hepatic adaptation to a KD and highlight the regulatory role of C. perfringens in ketonic states.
    Keywords:  Clostridium perfringens; Ketogenic diet; bile acids; gut microbiota; hyperketonemia; ketogenesis
    DOI:  https://doi.org/10.1080/19490976.2025.2496437
  2. Nutr Res. 2025 Mar 26. pii: S0271-5317(25)00043-0. [Epub ahead of print]137 56-70
      This meta-analysis aimed to quantitatively assess the effects of ketone intervention on cardiac function and structure in rodents with heart failure (HF). We hypothesized that ketone intervention could enhance the cardiac function and structure in HF. We systematically searched PubMed, Cochrane Library, and Embase databases for relevant studies up to April 13, 2024. Ketone therapy encompassed a ketogenic diet, ketone esters, medium-chain triglycerides, and β-hydroxybutyrate. The effect measures are mainly expressed as standardized mean difference (SMD) and 95% confidence interval (CI). Our meta-analysis included 24 animal studies. Ketone therapy significantly improved left ventricular ejection fraction (SMD: 1.31, 95% CI: 0.79-1.82, I2 = 77%), cardiac output (SMD: 0.70, 95% CI: 0.28-1.11, I2 = 0%), and ameliorated myocardial hypertrophy (SMD: -1.95, 95% CI: -2.76 to -1.13, I2 = 76%), myocardial fibrosis (SMD: -0.87, 95% CI: -1.60 to -0.15, I2 = 68%), and ventricular remodeling in HF rodents. Subgroup analysis indicated that ketone intervention worsened myocardial fibrosis in non-HF rodents (SMD: 0.86, 95% CI: 0.09-1.63, I2 = 78%) and had no significant effect on cardiac function. Additionally, further subgroup analysis indicated that ketogenic diet significantly alleviated cardiac hypertrophy and fibrosis, whereas ketone esters did not yield significant effects. The effect of ketone on left ventricular ejection fraction strengthened with the duration of intervention. Our results suggested that ketone therapy significantly improved the cardiac systolic function and structure in rodents with HF, and had no effect in rodents non-HF. Thus, ketone intervention may be a promising treatment for HF patients.
    Keywords:  Cardiac function and structure; Heart failure; Ketone intervention; Mechanism; Meta-analysis; Rodents
    DOI:  https://doi.org/10.1016/j.nutres.2025.03.008
  3. Diabetes Care. 2025 Apr 23. pii: dc250125. [Epub ahead of print]
       OBJECTIVE: We aimed to determine if routine capillary blood ketone testing on well days predicts future diabetic ketoacidosis (DKA) in type 1 diabetes (T1D) using sodium-glucose cotransporter inhibitors (SGLTi).
    RESEARCH DESIGN AND METHODS: We examined previously collected data from empagliflozin-assigned participants in a T1D trial that included weekly fasted ketone levels. Over 6-12 months, ketone levels were subdivided into 28-day periods, and the outcome was subsequent adjudicated DKA or severe ketosis.
    RESULTS: Among 1,194 participants, 325 had 49 DKA and 568 severe ketosis events. On-treatment maximum ketone levels were higher in the 28 days before an outcome compared with levels in those without an outcome, with area under receiver operating characteristic curve of 0.76 (95% CI 0.71-0.82). Maximum ketone level ≥0.8 mmol/L had sensitivity of 66.0%, specificity of 79.6%, and diagnostic odds ratio of 7.6.
    CONCLUSIONS: Routine surveillance of capillary ketone levels in T1D using SGLTi may represent a DKA mitigation strategy and implies a potential threshold for continuous ketone monitoring.
    DOI:  https://doi.org/10.2337/dc25-0125
  4. Front Neurosci. 2025 ;19 1489407
       Introduction: Ketogenic diet (KD), a high-fat, low-carbohydrate, and adequate protein diet, is a non-pharmacological treatment for refractory epilepsy. However, their mechanism of action is not fully understood. The cation-chloride cotransporter, KCC2, transports chloride out of neurons, thus contributing to the intraneuronal concentration of chloride. Modifications in KCC2 expression by KD feeding could explain the beneficial effect of this diet on epilepsy. This study aimed to determine the impact of KD on KCC2 expression in dentate gyrus layers and Cornu Ammonis 3 (CA3) strata of rats with seizures induced by amygdaloid kindling.
    Materials and methods: Male Sprague Dawley rats were fed a normal diet (ND) or KD from postnatal day 24 until the end of the experiment. At 6 weeks after the start of the diets, rats were subjected to an amygdala kindling epilepsy model, sham or remain intact. Glucose and β-hydroxybutyrate concentrations were quantified. The after-discharge duration (ADD), latency, and duration of stages of kindling were evaluated. In addition, KCC2 expression was evaluated using optical density. A Pearson bivariate correlation was used to determine the relationship between KCC2 expression and ADD.
    Results: At the end of the experiment, the KD-fed groups showed a reduction in glucose and an increase in β-hydroxybutyrate. KD reduced ADD and increased latency and duration of generalized seizures. In ND-fed animals, kindling reduced KCC2 expression in all three layers of the dentate gyrus; however, in KD-fed animals, no changes were observed. KD treatment increased KCC2 expression in the kindling group. In CA3, the pyramidal and lucidum strata showed an increase of KCC2 in KD-fed groups. Besides, the kindling had lower levels of KCC2 than the sham and intact groups. In all layers of the dentate gyrus and pyramidal and lucidum CA3 strata, the correlation indicated that the higher the KCC2 expression, the shorter the ADD during generalized seizures.
    Conclusion: KD reduces ADD in generalized seizures. In addition, KD has a putative neuroprotective effect by preventing the kindling-induced reduction of KCC2 expression in the molecular, granule, and hilar dentate gyrus layers and pyramidal and lucidum CA3 strata. Increased KCC2 expression levels are related to a shorter duration of generalized seizures.
    Keywords:  CA3; KCC2; dentate gyrus; ketogenic diet; kindling; rat
    DOI:  https://doi.org/10.3389/fnins.2025.1489407
  5. Sports Med. 2025 Apr 21.
       BACKGROUND: In response to exercise, protein kinases and signaling networks are engaged to blunt homeostatic threats generated by acute contraction-induced increases in skeletal muscle energy and oxygen demand, as well as serving roles in the adaptive response to chronic exercise training to blunt future disruptions to homeostasis. High-intensity interval training (HIIT) is a time-efficient exercise modality that induces superior or similar health-promoting skeletal muscle and whole-body adaptations compared with prolonged, moderate-intensity continuous training (MICT). However, the skeletal muscle signaling pathways underlying HIIT's exercise intensity-specific adaptive responses are unknown.
    OBJECTIVE: We mapped human muscle kinases, substrates, and signaling pathways activated/deactivated by an acute bout of HIIT versus work-matched MICT.
    METHODS: In a randomized crossover trial design (Australian New Zealand Clinical Trials Registry number ACTRN12619000819123; prospectively registered 6 June 2019), ten healthy male participants (age 25.4 ± 3.2 years; BMI 23.5 ± 1.6 kg/m2; V˙O2max 37.9 ± 5.2 ml/kg/min, mean values ± SD) completed a single bout of HIIT and MICT cycling separated by ≥ 10 days and matched for total work (67.9 ± 10.2 kJ) and duration (10 min). Mass spectrometry-based phosphoproteomic analysis of muscle biopsy samples collected before, during (5 min), and immediately following (10 min) each exercise bout, to map acute temporal signaling responses to HIIT and MICT, identified and quantified 14,931 total phosphopeptides, corresponding to 8509 phosphorylation sites.
    RESULTS: Bioinformatic analyses uncovered exercise intensity-specific signaling networks, including > 1000 differentially phosphorylated sites (± 1.5-fold change; adjusted P < 0.05; ≥ 3 participants) after 5 min and 10 min HIIT and/or MICT relative to rest. After 5 and 10 min, 92 and 348 sites were differentially phosphorylated by HIIT, respectively, versus MICT. Plasma lactate concentrations throughout HIIT were higher than MICT (P < 0.05), and correlation analyses identified > 3000 phosphosites significantly correlated with lactate (q < 0.05) including top functional phosphosites underlying metabolic regulation.
    CONCLUSIONS: Collectively, this first global map of the work-matched HIIT versus MICT signaling networks has revealed rapid exercise intensity-specific regulation of kinases, substrates, and pathways in human skeletal muscle that may contribute to HIIT's skeletal muscle adaptations and health-promoting effects.  Preprint: The preprint version of this work is available on medRxiv, https://doi.org/10:1101/2024.07.11.24310302 .
    DOI:  https://doi.org/10.1007/s40279-025-02217-2
  6. Metabolism. 2025 Apr 21. pii: S0026-0495(25)00139-8. [Epub ahead of print]169 156270
       BACKGROUND: Protein oxidation (PROTOX) typically accounts for the smallest fraction of daily energy expenditure (24hEE) in humans compared to carbohydrate and lipid oxidation. However, inter-individual differences in PROTOX may explain differences in fuel partitioning and body weight change. We aimed to elucidate the physiological determinants of PROTOX under controlled 24-h dietary conditions, including eucaloric feeding, fasting, and overfeeding diets with variable protein content.
    METHODS: Eighty-six weight-stable healthy volunteers with normal glucose regulation (67 M/19F; age: 37 ± 10 years; BMI: 26.7 ± 4.5 kg/m2, body fat by DXA: 29.0 ± 9.8 %) underwent 24hEE measurements by whole-room calorimetry during energy balance (20 % protein, 50 % carbohydrate), different overfeeding diets (200 % of the daily eucaloric requirement), including three normal-protein (20 %) diets (balanced: 50 % carbohydrate; high-carbohydrate: 75 % carbohydrate; high-fat: 60 % fat), low-protein (3 %) and high-protein (30 %), and 24-h fasting in a randomized crossover design. Urine samples were collected during each 24-h dietary intervention for quantification of PROTOX and catecholamine excretion rates by nitrogen excretion and high-performance liquid chromatography, respectively.
    RESULTS: PROTOX during energy balance (mean ± SD: 372 ± 78 kcal/day) was positively associated with protein intake (r = 0.39, p < 0.001), fat free mass (r = 0.35, p < 0.001), but not with fat mass (p = 0.24). Higher PROTOX was associated with higher 24-h urinary norepinephrine (partial r = 0.27, p = 0.01), but not epinephrine (p = 0.48), excretion rates. During normal-protein diets, higher PROTOX was associated with lower lipid oxidation, but showed no association with carbohydrate oxidation. Inter-individual variability in PROTOX did not predict changes in weight or body composition over two years.
    CONCLUSION: Dietary protein content, lean body mass, and sympathetic nervous system activity are key determinants of PROTOX. Although PROTOX did not predict free-living weight gain, increased PROTOX is associated with decreased lipid oxidation, underscoring its role in fuel partitioning and whole-body energy and substrate balance.
    Keywords:  Energy expenditure; Epinephrine; Lipid oxidation; Norepinephrine; Protein leverage; Protein oxidation; Weight gain
    DOI:  https://doi.org/10.1016/j.metabol.2025.156270
  7. Protein Sci. 2025 May;34(5): e70129
      β-hydroxybutyrate binding proteins (BHBBPs) are a newly identified group of periplasmic solute-binding proteins (SBPs) that interact with β-hydroxybutyrate (BHB), a key physiological metabolite. In this study, we systematically characterized the interaction properties of both previously reported and newly identified BHBBPs, including "NovoS" and "EDC10" from Gram-negative bacteria. Following recombinant production, we assessed the specificity and affinity of these proteins against a library of 23 different metabolites using a label-free derivative of differential scanning fluorimetry (nanoDSF). Positive interactions were further evaluated for their binding affinity via tryptophan fluorescence spectroscopy, which confirmed D/L-BHB as the preferred ligand for all proteins, with slight enantioselectivity. BHBBPs also exhibited binding to other compounds such as acetoacetate, D/L-α-hydroxybutyrate, L-lactate, and pyruvate, albeit with reduced affinity. These findings expand the classification of BHBBPs, suggesting that similar proteins and associated transporters may be widespread in prokaryotes involved in the carbon cycle of polyhydroxybutyrate. Guided by the crystal structure of the homologous BMA2936 protein, we introduced targeted point mutations in conserved polar residues of the BHBBPs EDC24 and NovoS. It was determined through this experimental pipeline that their affinity towards BHB was reduced by a factor between 25 and 750, shifting their binding constants towards the millimolar range. Collectively, the affinities of both wild-type and mutant proteins span 4 orders of magnitude, from nanomolar to millimolar recognition of BHB. Leveraging the versatility of SBP-based biosensing, these receptors and their wide affinity range could facilitate the development of effective bioanalytical tools for BHB detection in diverse physiological environments.
    Keywords:  biosensor; diabetic ketoacidosis; ketone; nano differential scanning fluorimetry; nanoDSF; site‐directed mutagenesis; solute‐binding proteins; β‐hydroxybutyrate binding proteins
    DOI:  https://doi.org/10.1002/pro.70129
  8. Front Aging Neurosci. 2025 ;17 1552905
      Alzheimer's disease (AD) significantly reduces the quality of life of patients and exacerbates the burden on their families and society. Resistance exercise significantly enhances the overall cognitive function of the elderly and patients with AD while positively improving memory, executive function, and muscle strength, reducing fall risks, and alleviating psychological symptoms. As AD is a neurodegenerative disorder, some nerve factors are readily activated and released during exercise. Therefore, several prior studies have concentrated on exploring the molecular mechanisms of resistance exercise and their impact on brain function and neural plasticity. Recent investigations have identified an intrinsic relationship between individuals with AD and the pathological mechanisms of skeletal muscle atrophy, establishing a correlation between patients with AD cognitive level and skeletal muscle content. Resistance exercise primarily targets the skeletal muscle, which improves cognitive impairment in patients with AD by reducing vascular and neuroinflammatory factors and further enhances cognitive function in patients with AD by restoring the structural function of skeletal muscle. Furthermore, the effects of resistance training vary among distinct subgroups of cognitive impairment. Individuals exhibiting lower cognitive function demonstrate more pronounced adaptive responses in physical performance over time. Consequently, further investigation is warranted to determine whether tailored guidelines-such as variations in the frequency and duration of resistance exercise-should be established for patients with varying levels of dementia, in order to optimize the benefits for those experiencing cognitive impairment. This study aimed to review the relationship between AD and skeletal muscle atrophy, the impact of skeletal muscle atrophy on AD cognition, the mechanism by which resistance exercise improves cognition through skeletal muscle improvement, and the optimal resistance exercise mode to elucidate the additional advantages of resistance exercise in treating cognitive function in patients with AD and skeletal muscle atrophy.
    Keywords:  Alzheimer's disease; cognitive function; neuromuscular; resistance exercise; skeletal muscle atrophy
    DOI:  https://doi.org/10.3389/fnagi.2025.1552905
  9. Mol Neurobiol. 2025 Apr 24.
      We and others have previously demonstrated that hypoxia-inducible factor alpha (HIF-1α) stabilization through diet-induced ketosis plays a vital role during brain ischemic injury. We have recently reported that ketosis-stabilized HIF-1α regulates the inflammatory response and contributes to neuroprotection in a rat stroke model. In the current investigation, we examined the downstream mechanism by which the ketogenic (KG) diet protects against brain damage after stroke in mice. Six- to seven-week-old male mice were fed the standard diet (SD) or the KG diet to mimic the metabolic state of chronic ketosis. After 4 weeks, mice were subjected to photothrombotic ischemic stroke. Behavior analysis was recorded at 24 h, 48 h, and 72 h post-stroke. After 72 h, mice were euthanized for infarction, brain edema, hemorrhage, and molecular analysis. Our results showed that the KG diet significantly alleviated infarction, brain edema, and hemorrhage; improved the neurobehavioral outcomes; and attenuated ischemic stroke-induced oxidative/nitrative stress and apoptotic markers at 72 h post-stroke. Further, the KG diet upregulated the HIF-1α and interleukin (IL)-10 expression and inhibited thioredoxin-interacting protein (TXNIP), NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation and pro-inflammatory cytokine expression compared to SD-fed mice after stroke. We showed that the KG diet did not show neuroprotection in the NLRP3 knockout mice after stroke. Our current study demonstrates that the KG diet exerts neuroprotective effects by inhibiting TXNIP-NLRP3 inflammasome, mainly dependent on heightening the upregulation of IL-10 via HIF-1α stabilization. Thus, the KG diet might be considered a new therapeutic strategy for ischemic patients.
    Keywords:  HIF- 1α; Ischemic stroke; Ketogenic diet; NLRP3 inflammasome
    DOI:  https://doi.org/10.1007/s12035-025-04943-0
  10. Cell Commun Signal. 2025 Apr 22. 23(1): 192
      There has been a recent expansion in our understanding of DNA-sensing mechanisms. Mitochondrial dysfunction, oxidative and proteostatic stresses, instability and impaired disposal of nucleoids cause the release of mitochondrial DNA (mtDNA) from the mitochondria in several human diseases, as well as in cell culture and animal models. Mitochondrial DNA mislocalized to the cytosol and/or the extracellular compartments can trigger innate immune and inflammation responses by binding DNA-sensing receptors (DSRs). Here, we define the features that make mtDNA highly immunogenic and the mechanisms of its release from the mitochondria into the cytosol and the extracellular compartments. We describe the major DSRs that bind mtDNA such as cyclic guanosine-monophosphate-adenosine-monophosphate synthase (cGAS), Z-DNA-binding protein 1 (ZBP1), NOD-, LRR-, and PYD- domain-containing protein 3 receptor (NLRP3), absent in melanoma 2 (AIM2) and toll-like receptor 9 (TLR9), and their downstream signaling cascades. We summarize the key findings, novelties, and gaps of mislocalized mtDNA as a driving signal of immune responses in vascular, metabolic, kidney, lung, and neurodegenerative diseases, as well as viral and bacterial infections. Finally, we define common strategies to induce or inhibit mtDNA release and propose challenges to advance the field.
    Keywords:  Circulating cell-free DNA; DNA-sensing receptors; Inflammation; Innate immunity; Mitochondria; Mitochondrial DNA
    DOI:  https://doi.org/10.1186/s12964-025-02042-0
  11. J Sports Med Phys Fitness. 2025 Apr 23.
       BACKGROUND: A single sprint interval training (SIT) session is known to have positive effects on fat metabolism by increasing postexercise oxygen consumption (V̇O<inf>2</inf>) and fat oxidation. A short-term high-fat diet intervention has positive effects on fat oxidation pre- and postsubmaximal exercise sessions. However, there is no study on the effects of the combination of diet and a SIT session on fat oxidation. The study aimed to investigate the effect of different short-term diet modifications on fat oxidation following a SIT session.
    METHODS: Nine healthy active males (24.3±5.27 years) participated in this investigation. Following isocaloric normal (NOR), high carbohydrate (CHO), and high fat (FAT) diet interventions with a weekly interval, participants performed an SIT session (6 repeats × Wingate all-out sprints with 4.5 minutes of rest in-between bouts). V̇O<inf>2</inf> and V̇CO<inf>2</inf> were measured by a gas analyzer throughout a 2-hour recovery period.
    RESULTS: There was no significant time × session interaction for fat oxidation, V̇O<inf>2</inf>, total energy expenditure, and respiratory exchange ratio. The resting fat oxidation (g.min-1) was statistically greater in the FAT diet (0.12±0.04) than in the CHO (0.08±0.02, P=0.012) and NOR (0.08±0.02, P=0.009) diets. Only a 2-hour postexercise fat oxidation (g.min-1) (0.22±0.05) was statistically higher for the FAT diet compared to the CHO diet (0.15±0.05; P=0.006).
    CONCLUSIONS: While the study showed significant differences in fat oxidation between diets, the magnitude of the difference was so small (~0.04 g/min) that it may not have a truly effective 'real world' implication for burning extra calories.
    DOI:  https://doi.org/10.23736/S0022-4707.25.16201-4
  12. J Leukoc Biol. 2025 Apr 23. pii: qiaf014. [Epub ahead of print]117(4):
      The NOD-like receptor family, particularly the protein 3 that contains the pyrin domain (NLRP3), is an intracellular sensing protein complex responsible for detecting patterns associated with pathogens and injuries. NLRP3 plays a crucial role in the innate immune response. Currently, a wide range of research has indicated the crucial importance of NLRP3 in various inflammatory conditions. Similarly, the NLRP3 inflammasome plays a significant role in preserving intestinal balance and impacting the advancement of diseases. In addition, several randomized trials have demonstrated the safety and efficacy of targeting NLRP3 in the treatment of colitis, colorectal cancer, and related diseases. This review explores the mechanisms of NLRP3 assembly and activation in the gut. We describe its pathological significance in intestinal diseases. Finally, we summarize current and future therapeutic approaches targeting NLRP3 for intestinal diseases.
    Keywords:  NLRP3; activation; intestinal disease; intestinal epithelial barrier; intestinal immunity; pharmacological targeting
    DOI:  https://doi.org/10.1093/jleuko/qiaf014
  13. Mitochondrion. 2025 Apr 18. pii: S1567-7249(25)00039-X. [Epub ahead of print] 102042
      Mitochondria are membrane-bound organelles of eukaryotic cells that play crucial roles in cell functioning and homeostasis, including ATP generation for cellular energy. Mitochondrial function is associated with several complex diseases and disorders, including cardiovascular, cardiometabolic, neurodegenerative diseases and some cancers. The risk for these diseases and disorders is often associated with mitochondrial dysfunction, particularly the quantitative and qualitative features of the mitochondrial genome. Emerging results implicate mito-nuclear crosstalk as the mechanism by which mtDNA variation affects complex disease outcomes. Experimental approaches are emerging for the targeting of mitochondria as a potential therapeutic for several of these diseases, particularly in the form of mitochondrial transplantation. Current approaches to mitochondrial transplantation generally involve isolating healthy mitochondria from donor cells and introducing them to diseased recipients towards amelioration of mitochondrial dysfunction. Using such a protocol, several reports have shown recovery of mitochondrial function and improved disease outcomes post-mitochondrial transplantation, highlighting its potential as a therapeutic method for several complex, severe and debilitating diseases. Additionally, the mitochondrial genome can be modified prior to transplantation to target disease-associated site-specific mutations and to reduce the ratio of mutant-to-WT alleles. These promising results may underlie the potential impact of mitochondrial transplantation on mito-nuclear genome interactions in the setting of the disease. Further, we recommend that mitochondrial transplantation experimentation include an assessment of potential impacts on remodelling of the nuclear genome, particularly the nuclear epigenome and transcriptome. Herein, we review these and other triumphs and challenges of mitochondrial transplantation as a potential novel therapeutic for mitochondria-associated diseases.
    Keywords:  Mito-nuclear crosstalk; Mitochondria; Mitochondrial DNA; Mitochondrial transplantation; Nuclear epigenome; Nuclear transcriptome
    DOI:  https://doi.org/10.1016/j.mito.2025.102042