Search Results (197)

Adipotoxicity is a major contributor to insulin resistance and type 2 diabetes, and increasing evidence highlights the gut–adipose axis as a promising therapeutic target. Soursop (Annona muricata) is rich in phytochemicals that can be biotransformed by the gut microbiota into bioactive metabolites with metabolic benefits. The present study investigated whether metabolites generated by in vitro fecal fermentation of soursop fruit (SWSF) and peel (SWSFP) protect against fructose-induced adipotoxicity. SWSF and SWSFP were fermented with rat fecal microbiota, and the resulting metabolites were evaluated in an ex vivo fructose-induced adipotoxicity model using perigonadal white adipose tissue. Activities of enzymes involved in glucose metabolism, the polyol pathway, glutathione metabolism, glyoxalase-1 activity, purinergic signaling, and inflammatory lipid metabolism were determined. GC–MS-based metabolomics and pathway enrichment analyses were performed on fecal and adipose tissues. Soursop fermentation significantly remodeled the fecal metabolome, enriching metabolites associated with fatty acid metabolism, glycerolipid metabolism, β-oxidation, sterol metabolism, and arachidonic acid metabolism. Fructose-induced adipotoxicity disrupted glucose metabolism, activated the polyol pathway, impaired glutathione metabolism and glyoxalase-1 activity, suppressed ATPase and ENTPDase activities, and elevated 5-LOX and 12/15-LOX activities. Treatment with soursop-enriched fecal metabolites significantly reversed these alterations in a dose-dependent manner. Adipose metabolomics further demonstrated restoration of pathways associated with fatty acid biosynthesis, mitochondrial β-oxidation, glycerolipid metabolism, steroid biosynthesis, and polyunsaturated fatty acid metabolism, indicating improved lipid homeostasis and reduced inflammatory lipid signaling. SWSF and SWSFP generally exhibited greater metabolic protection than the reference antioxidant compound, gallic acid. Soursop-derived gut metabolites attenuate fructose-induced adipotoxicity by coordinately restoring glucose metabolism, redox homeostasis, carbonyl detoxification, purinergic signaling, and lipid metabolism through the gut–adipose axis. These results suggest soursop as a potential functional food for preventing and managing adipose tissue dysfunction and metabolic disorders. Full article

Salt stress severely limits wheat growth and seed yield; however, the mechanisms underlying plant-derived smoke (PDS)-induced salt tolerance remain unclear. The present study performs membrane proteomics to clarify how PDS solution enhances salt tolerance in wheat. Immunoblot analysis of subcellular marker proteins confirms successful enrichment of membrane fractions. Principal component analysis shows that 200 mM NaCl markedly alters membrane-protein composition in wheat roots, whereas 2000 ppm PDS solution largely restores these changes even under salt stress. At the protein level, mitochondrial ascorbate peroxidase increases in roots under salt stress but decreases with PDS-solution treatment, while leaves show the opposite trend. Salt stress reduces ATP content and H⁺-ATPase abundance; PDS-solution treatment restores both to near-control levels. In contrast, aquaporin levels increase under salt stress but decline after PDS-solution application. In addition, the expression of ammonium transporter was downregulated significantly under salt stress but recovered with PDS-solution treatment. These results suggest that PDS solution may confer salt-stress tolerance to wheat by regulating energy metabolism, water permeability, and ammonium absorption in the root membrane. Full article

Cellular senescence is characterized by the accumulation of reactive oxygen species (ROS), and the selective elimination of excessive ROS remains a key therapeutic challenge. Through antioxidant screening, we identified the pyrazole-based small molecule KB3409 as a potent regulator that reduces ROS levels in senescent fibroblasts. To elucidate its mechanism of action, we performed target identification and found that KB3409 directly binds to valosin-containing protein (VCP) and reticulocalbin-2 (RCN2). Functionally, KB3409 acts as an allosteric activator of VCP, enhancing its ATPase activity and promoting autophagic flux. This activation facilitates the selective clearance of dysfunctional mitochondria, thereby improving mitochondrial quality control and limiting ROS generation at its source. Concurrently, KB3409 modulates RCN2-dependent Ca²⁺ homeostasis, alleviating mitochondrial Ca²⁺ overload and suppressing the opening of the mitochondrial permeability transition pore (mPTP). This coordinated regulation preserves mitochondrial structural integrity and sustains oxidative phosphorylation efficiency. Collectively, these findings identified the novel mechanism in which KB3409 restores mitochondrial function, reduces ROS levels, and functionally reverses cellular senescence phenotypes. Full article

Oxidative stress is closely associated with mitochondrial dysfunction and contributes to the development of several human diseases. Among antioxidant compounds, ASC and NAC are widely used for their cytoprotective and redox-regulating properties; however, their direct effects on specific aspects of mitochondrial bioenergetics are only partially characterized. In the present study, we investigated the effects of ASC and NAC, individually and combined, on Mg²⁺-dependent F₁F_O-ATPase hydrolysis, mitochondrial free thiol content and respiration in isolated swine heart mitochondria. ASC significantly stimulated F₁F_O-ATPase activity in a concentration-dependent manner, whereas kinetic analysis indicated a mixed uncompetitive activation mechanism. In contrast, NAC alone did not significantly affect F₁F_O-ATPase activity but abolished the stimulatory effect of ASC when the two compounds were combined. Both ASC and NAC increased mitochondrial free thiol content, although no change was observed under combined treatment conditions. Mitochondrial oxygen consumption analysis revealed substrate-dependent effects of the two antioxidants on electron transport. Overall, ASC and NAC exerted distinct direct actions on isolated mitochondria, and their combination did not produce additive or synergistic effects. These findings provide new insights into the direct modulation of mitochondrial function by antioxidant compounds and may contribute to expanding understanding of their potential therapeutic and dietary supplement applications, particularly when combined. Full article

Potassium is the predominant intracellular cation and plays a fundamental role in maintaining membrane potential, cellular metabolism, enzyme activity, protein synthesis, acid–base homeostasis, and mitochondrial bioenergetics. Although hypokalemia is readily identified by decreased serum potassium concentration, serum potassium represents only a small fraction of total-body potassium stores and therefore may not accurately reflect intracellular potassium status. Consequently, chronic total-body potassium depletion and intracellular potassium deficiency may remain clinically unrecognized despite serum potassium concentrations within the reference range. Growing experimental and clinical evidence suggests that disturbances of potassium homeostasis are associated with multiple metabolic abnormalities involving the cardiovascular, neuromuscular, endocrine, renal, and gastrointestinal systems. Intracellular potassium depletion has been associated with mitochondrial dysfunction, oxidative stress, impaired insulin secretion and insulin sensitivity, metabolic alkalosis, chronic low-grade inflammation, and anabolic resistance. However, these relationships are complex and frequently bidirectional, indicating that potassium deficiency should be regarded as one component of an integrated metabolic network rather than an isolated pathogenic mechanism. This narrative review critically summarizes current evidence regarding the physiological regulation of potassium homeostasis, distinguishes hypokalemia from total-body potassium depletion and intracellular potassium deficiency, and discusses the mechanisms through which potassium depletion may contribute to systemic metabolic dysfunction. Particular attention is given to the clinical manifestations, diagnostic evaluation, and current therapeutic approaches to disorders of potassium homeostasis. Finally, important knowledge gaps are highlighted, including the need for reliable biomarkers of intracellular potassium deficiency and prospective studies evaluating whether correction of chronic potassium depletion improves long-term metabolic and clinical outcomes beyond normalization of serum potassium concentration. Full article

Mitochondrial Lon peptidase 1 (LONP1) is an ATP-dependent AAA⁺ (ATPases associated with diverse cellular activities) protease that has emerged as a key regulator of mitochondrial proteostasis, with functions extending beyond protein quality control. In addition to degrading misfolded and oxidized proteins, LONP1 coordinates mitochondrial DNA maintenance, metabolic remodeling, and stress-responsive signaling. Recent structural and functional advances have expanded the biological significance of LONP1 beyond protein quality control, highlighting its roles in mitochondrial metabolism, genome maintenance, and stress responses. LONP1 dysregulation is increasingly implicated in cancer, metabolic disorders, neurodegeneration, and aging, where it exerts context-dependent effects on cell survival and disease progression. In cancer, LONP1 supports metabolic plasticity, redox adaptation, and therapeutic resistance, whereas in degenerative conditions, its decline contributes to mitochondrial dysfunction and tissue damage. Here, we synthesize recent insights into the structure, mechanisms, and biological functions of LONP1 and discuss their implications for human disease. We further discuss emerging therapeutic strategies and key challenges for targeting LONP1 in human disease. Full article

Background/Objectives: Obesity-associated non-alcoholic fatty liver disease (NAFLD) drives systemic metabolic stress and accelerates chronic kidney disease, yet the mechanistic links remain unclear. Mitochondrial dysfunction has emerged as a central mediator of obesity-induced organ injury. Here, we investigated renal mitochondrial remodeling in a rat model of obesity-associated NAFLD (Ob-NAFLD) and examined the effects of metformin. Methods: Female Zucker rats (obese fa/fa and lean Fa/Fa) were fed an AIN-93G diet for eight weeks, followed by 10 weeks of metformin treatment in designated groups. Kidney tissues were analyzed using biochemical assays, immunoblotting, blue native PAGE, in-gel activity assays, and histological evaluation. Results: In Ob-NAFLD rats, renal ATP levels were elevated despite reduced electron transport chain (ETC) Complex III and increased Complex V expression, reflecting compensatory ATP synthase hyperactivity uncoupled from efficient oxidative phosphorylation. Mitochondrial dynamics were disrupted such that inhibitory phosphorylation of DRP1 was reduced, promoting fission, and total OPA1 expression was decreased with a shift in short-to-long isoform balance, indicating impaired fusion and cristae remodeling. Notably, ATPase inhibitory factor 1 (IF1), a checkpoint that limits ATP synthase overdrive, remained stably expressed, suggesting an adaptive ceiling or failed protective control under chronic metabolic stress. Metformin partially alleviated bioenergetic stress by lowering ATP and modestly restoring Complex III, yet ETC imbalance and structural remodeling persisted, revealing the limitations of metabolic modulation alone. Conclusions: These findings position entrenched mitochondrial dysregulation as a mechanistic bridge linking obesity-driven liver disease to kidney injury. Therapeutic strategies combining metabolic interventions with targeted restoration of ETC coordination, mitochondrial dynamics, and regulatory checkpoints such as IF1 may be required to fully restore renal mitochondrial health and prevent the progression of metabolic kidney disease. Full article

Excitotoxicity is one of the factors that participates in neurodegeneration, impairing neuronal and glial cells’ function, and leading to the development of chronic neurodegenerative diseases. The main mechanism of action lies in the overstimulation of excitatory receptors, especially the NMDA (N-methyl-D-aspartic acid) receptor, by glutamate, which promotes a massive influx of Ca²⁺ that is not sufficiently buffered by the intracellular machinery, or not released by mechanisms such as Ca²⁺ ATPase and plasma membrane Ca²⁺/Na⁺ exchanger promoting, among other toxic effects, mitochondrial damage and an increase in reactive oxygen species (ROS). Notably, many cases reported of long COVID-19 describe significant brain alterations and neuropsychiatric disorders, including delirium, depression, etc., and patients required increased use of antidepressant or anxiolytic drugs, for example. In addition, emerging evidence links neurodegeneration as a potential long-term sequelae associated with an increased number of patients with cognitive disorders. This review analyzes data from the literature regarding brain alterations associated with post-COVID-19 syndrome and explores a potential link to the excitotoxicity pathways, due to its participation in neurodegeneration by homeostatic failure, and it is clearly present in various brain conditions, such as Alzheimer’s and Parkinson’s diseases. Full article

Tumour necrosis factor-alpha (TNF-α) disrupts bioenergetic homeostasis in skeletal muscle cells through the suppression of ion-dependent ATPase activities, mitochondrial depolarisation, and impairment of antioxidant defences. Carvacrol, a phenolic monoterpenoid constituent of thyme and oregano essential oil, has been shown to exert cytoprotective effects in TNF-α-challenged L6 rat myoblasts. The mechanistic basis of these effects, specifically the relationship between membrane-associated ATPase function, mitochondrial polarisation status, and transcriptional regulation of metabolic stress-response genes, has not been formally characterised. L6 rat myoblasts were exposed to TNF-α (10 ng/mL, 1 h), then treated with carvacrol (6.25 µg/mL, 24 h) in a post-inflammatory rescue paradigm. Cell viability (MTT), membrane integrity (LDH), ion-dependent ATPase activities (Na⁺/K⁺, Ca²⁺, Mg²⁺), antioxidant enzyme activities (catalase, SOD), mitochondrial membrane potential (Muse™ MitoPotential flow cytometry), and SIRT1/AMPK mRNA expression were quantified. TNF-α significantly suppressed Na⁺/K⁺, Ca²⁺, and Mg²⁺-dependent ATPase activities (all p < 0.001), consistent with impaired membrane-associated bioenergetic function. Post-TNF-α carvacrol treatment partially restored all three ATPase activities (p < 0.05) and reduced the proportion of mitochondrially depolarised cells from 31.65 ± 4.25% to 19.0 ± 2.6% (p < 0.05). LDH release, catalase activity, and SOD activity were also significantly modulated. At the transcriptional level, carvacrol increased SIRT1 mRNA by 1.6-fold and AMPK mRNA by 2.0-fold relative to TNF-α-treated cells. An integrative bioenergetic model is proposed in which carvacrol’s membrane-intercalating properties restore the phospholipid environment required for ATPase conformational cycling, attenuating the Ca²⁺ overload that drives mitochondrial permeability transition, and thereby partially preserving Δψm. Transcriptional upregulation of SIRT1 and AMPKα may represent an adaptive response to residual energetic stress. The mechanistic relationships among these endpoints and the causal contribution of SIRT1 and AMPK to observed bioenergetic changes require protein-level and pathway-specific experimental validation. Full article

Pomegranate peel is a food industry waste rich in polyphenols. To date, its effect in alleviating fatigue remains unclear. This study aimed to characterize the chemical composition of pomegranate peel polyphenols (PPPs), evaluate its antioxidant and anti-fatigue capacities, and investigate the underlying mechanism. In the current study, twenty main compounds, primarily flavonoids, phenolic acids, and anthocyanins, were identified from PPPs using LC-MS/MS. In H₂O₂-induced HepG2 cells, PPPs promoted cellular repair and reduced the production of intracellular malondialdehyde (MDA) and reactive oxygen species (ROS) via enhancing the activity of antioxidant enzymes (SOD, CAT, and GSH-Px). In the endurance swimming-induced fatigue mice model, PPPs prolonged mice exhaustion times, reduced accumulation of fatigue-related metabolites (BUN, LA, BA, LDH and CK), and alleviated liver and muscle tissue damage. Mechanistically, PPPs mitigated oxidative stress via activation of the Keap1/Nrf2 pathway, leading to increased expression of hemeoxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). Furthermore, PPPs stimulated energy metabolism by activating the AMPK/PGC-1α/PPAR-α pathway, promoting mitochondrial biogenesis, enhancing glycogen storage, increasing ATPase activity (Na⁺-K⁺-ATPase, Ca²⁺-Mg²⁺-ATPase, and T-ATPase) and accelerating lipid β-oxidation. These findings suggest that PPPs is a promising anti-fatigue supplement and could be further utilized in the nutritional industry. Full article

To address cryodamage in Culter alburnus sperm, this study evaluated the effects of trehalose supplementation in a conventional cryomedium (D-15 + 10% ethylene glycol). Six experimental groups were established: fresh sperm (G1), a conventional cryomedium (G2), groups supplemented with 10, 100, or 200 mmol/L trehalose (G3–G5), and a control group with extender only (G6). The group with 100 mmol/L trehalose (G4) was associated with improved post-thaw motility parameters (activation rate, movement time, and lifespan) and higher antioxidant (superoxide dismutase and catalase) and energy metabolism (ATPase, succinate dehydrogenase, lactate dehydrogenase) enzyme activities. Ultrastructural damage in G4 included partial plasma membrane rupture and mitochondrial swelling, while G6 exhibited additional damage features including membrane disintegration, mitochondrial disruption, and flagellar fracture. Proteomic analysis revealed that, compared to G1, G4 exhibited higher abundance of proteins (e.g., Histone H2A, cytochrome c oxidase, profilin) involved in structural integrity and energy homeostasis, whereas G6 showed signatures of oxidative stress and metabolic dysfunction (lower abundance of NADH dehydrogenase and higher abundance of calcium-transporting ATPase and glutathione S-transferase). In conclusion, 100 mmol/L trehalose was associated with improved cryopreservation outcomes, and the proteins identified provide a basis for further investigation. This approach offers a framework for refining germplasm conservation strategies in aquaculture. Full article

Delayed effects of acute radiation exposure (DEARE), including radiation pneumonitis (lung-DEARE), develop weeks to months after radiation exposure. Pathway-targeted biomarkers that capture early oxidative stress and cell death could improve risk stratification and provide objective measures of mitigator efficacy. The objective was to test whether molecular lung imaging predicts long-term survival and mitigator response after irradiation. Rats received 13.5 Gy leg-out partial-body irradiation with a subset treated with the radiation-injury mitigator lisinopril. Rats underwent lung imaging at weeks 2 and 4 post-irradiation with ^99mTc-duramycin (cell death) and ^99mTc-HMPAO (oxidative stress). Plasma mitochondrial damage-associated molecular patterns (mtDAMPs) were also measured. Irradiation reduced survival with animals evidencing significant pleural effusion as an indication of radiation pneumonitis, which was mitigated with lisinopril as previously shown. Lung uptake of both imaging biomarkers increased in irradiated rats between weeks 2 and 4, consistent with worsening cell death and oxidative stress. Rats that succumbed by day 120 exhibited significantly larger increases in both biomarkers than the survivors. A predictive test was developed that predicted death by day 120 with ~70% sensitivity and specificity. Plasma mtDAMPs (ND1/2 and ATPase 6/8) increased following irradiation, and the D-loop increase from week 2 to 3 separated outcomes (increase in nonsurvivors versus decrease in survivors). Both imaging and mtDAMPs data from lisinopril-treated animals showed blunted responses. Early dual-tracer molecular lung imaging predicted long-term survival after radiation exposure and tracked mitigation with lisinopril. Circulating mtDAMPs may provide complementary systemic information to further strengthen early risk stratification after radiation exposure. Full article

Osmotic stress affects ion transport and cell hydration, potentially disrupting redox homeostasis through altered proteostasis and mitochondrial metabolism. However, how immune hemocytes coordinate volume regulation with these stress-linked processes, particularly oxidative stress and antioxidant responses, remains unclear in crustaceans. This study integrated quantitative cytology, RNA sequencing, and network analysis to profile hemocyte volume plasticity in the euryhaline shrimp Penaeus monodon across a salinity gradient. Hemocytes were incubated for 24 h in hypoosmotic, isosmotic, and hyperosmotic media, with significant volume shifts observed while maintaining membrane integrity and morphology. The permeability of solutes (urea and sorbitol) suggested that volume adjustment is coupled with solute transport. Transcriptomic analyses identified key salinity-responsive pathways, including oxidative phosphorylation, MAPK signaling, ribosome biogenesis, and antioxidant defense mechanisms, underscoring the activation of redox-regulatory systems under osmotic stress. Weighted gene co-expression network analysis highlighted ribosomal proteins as central hubs in a salinity-responsive module, with qRT-PCR confirming the co-regulation of these hubs alongside representative osmoregulatory and antioxidant genes (AQP4, Na⁺/K⁺-ATPase, HSP70, CHOP, and antioxidant enzymes). These findings reveal how hemocyte volume dynamics are coupled to redox regulation, providing a mechanistic framework for understanding osmotic stress–redox coupling in crustacean immune cells. Full article

Acetaminophen (APAP) overdose is a major cause of acute liver failure and can be fatal, often without early symptoms. Protein deficiency, arising from illness or inadequate diet, impairs growth, immunity, and tissue repair. Both conditions can harm the kidneys, yet the impact of energy imbalance on renal physiology remains unclear. In this study, APAP toxicity and a low-protein diet induced behavioral suppression and tissue damage, as evidenced by reduced whole-body, liver, and kidney weights in rats. In kidney mitochondria of rats exposed to only toxic APAP doses, ATP levels declined sharply while ADP and AMP increased. AMP deaminase and ATPases’ activities rose about twofold and 1.5-fold, respectively, whereas cytosolic 5′-nucleotidase activity fell nearly threefold, suggesting compensatory responses to disrupted energy balance. The strongest reductions in ATP and the greatest increases in AMP and ATPase activity occurred in APAP-intoxicated rats fed a low-protein diet. This combination also intensified lipid peroxidation and oxidative protein damage, evidenced by elevated TBARS, reduced protein SH-groups, and increased protein carbonyls. Overall, APAP intoxication with protein deficiency disrupts renal energy metabolism, leading to mitochondrial dysfunction and structural kidney injury. Nutritional status therefore critically influences drug-induced nephrotoxicity, and antioxidant strategies may help prevent damage under metabolic stress. Full article

Emerging research indicates that neuronal activity is maintained by an architectural system of protons in a multi-scale fashion. Proton architecture is formed when organelles (such as mitochondria, endoplasmic reticulum, lysosomes, synaptic vesicles, etc.) are coupled together to produce dynamic energy domains. Techniques have been developed to visualize protons in neurons; recent advances include near-atomic structural imaging of organelle interfaces using cryo-tomography and nanoscale resolution imaging of organelle interfaces and proton tracking using ultra-fast spectroscopy. Results of these studies indicate that protons in neurons do not diffuse randomly throughout the neuron but instead exist in organized geometric configurations. The cristae of mitochondrial cells create oscillating proton micro-domains that are influenced by the curvature of the cristae, hydrogen bonding between molecules, and localized changes in dielectric properties that result in time-patterned proton signals that can be used to determine the metabolic load of the cell and the redox state of its mitochondria. These proton patterns also communicate to the rest of the cell via hydrated aligned proton-conductive pathways at the mitochon-dria-endoplasmic reticulum junctions, through acidic lipid regions, and through nano-tethered contact sites between mitochondria and other organelles, which are typically spaced approximately 10–25 nm apart. Other proton architectures exist in lysosomes, endosomes, and synaptic vesicles. In each of these organelles, the V-ATPase generates steep concentration gradients across their membranes, controlling the rate of cargo removal from the lumen of the organelle, recycling receptors from the surface of the membrane, and loading neurotransmitters into the vesicles. Recent super-resolution pH mapping has indicated that populations of synaptic vesicles contain significant heterogeneity in the amount of protons they contain, thereby influencing the amount of neurotransmitter released per vesicle, the probability of vesicle release, and the degree of post-synaptic receptor protonation. Additionally, proton gradients in each organelle interact with the cytoskeleton: the protonation status of actin and microtubules influences filament stiffness, protein–protein interactions, and organelle movement, resulting in the formation of localized spatial structures that may possess some type of computational significance. At multiple scales, it appears that neurons integrate the proton micro-domains with mechanical tension fields, dielectric nanodomains, and phase-state transitions to form distributed computing elements whose behavior is determined by the integration of energy flow, organelle geometry, and the organization of soft materials. Alterations to the proton landscape in neurons (e.g., due to alterations in cristae structure, drift in luminal pH, disruption in the hydration-structure of the cell, or imbalance in the protonation of cytoskeletal components) could disrupt the intracellular signaling network well before the onset of measurable electrical or biochemical pathologies. This article will summarize evidence indicating that proton–organelle interaction provides a previously unknown source of energetic substrate for neural computation. Using an integrated approach combining nanoscale proton energy, organelle interface geometry, cytoskeletal mechanics, and AI-based multiscale models, this article outlines current principles and unresolved questions related to the subject area as well as possible new approaches to early detection and precise intervention of pathological conditions related to altered intracellular energy flow. Full article