Search Results (1,042)

Type 2 diabetes mellitus (T2DM) accounts for over 90% of diabetes cases, and T2DM-related sarcopenia is a growing concern. Carnosine, abundant in human skeletal muscle, helps maintain muscle quality and function. This study investigated whether carnosine deficiency contributes to T2DM-related sarcopenia and whether exogenous carnosine supplementation alleviates muscle atrophy. A mouse model of T2DM sarcopenia was established using streptozotocin combined with a high-fat diet. LC-MS metabolomics revealed a significant reduction in carnosine content in the gastrocnemius muscle of model mice. A C2C12 myotube atrophy model was induced by high-glucose (HG), and qRT-PCR showed altered expression of carnosine metabolism-related enzymes, suggesting disrupted carnosine homeostasis under T2DM conditions. Mechanistic investigations using immunofluorescence, Western blotting, transcriptome sequencing, mitochondrial staining, and molecular docking indicated that carnosine may alleviate high-glucose-induced myotube atrophy through the PI3K/AMPK/PGC-1α signaling pathway. In vivo, carnosine supplementation increased the number of mitochondria and the proportion of slow muscle fibers in gastrocnemius muscle, ameliorating the atrophic phenotype. These findings suggest that carnosine has potential as a candidate for intervention in T2DM-related sarcopenia, though further validation of its direct molecular targets is required. Full article

Oxidative stress has been recognized as a repeatedly validated pathophysiological factor in schizophrenia, but its mechanistic role and translational relevance remain incompletely defined. Prior work has advanced redox dysregulation, neuroinflammation, and NMDA receptor hypofunction as a putative central hub in schizophrenia. This narrative review proposes an evidence-weighted redox–mitochondria–immune framework that integrates peripheral biomarkers, magnetic resonance spectroscopy, postmortem findings, and preclinical mechanisms while explicitly distinguishing established observations from candidate pathways. Existing studies support increased oxidative damage and altered antioxidant buffering in schizophrenia, particularly involving the glutathione system. However, these abnormalities are neither uniform across disease stages nor equally represented across patient subgroups, and may be markedly prominent only in certain biological subgroups. Mechanistically, redox imbalance may interact with mitochondrial bioenergetic deficits and innate immune signaling; however, pathway-specific links such as cGAS-STING activation, nitrosative/peroxynitrite stress, and GPx4-ferroptosis should currently be treated as testable extensions rather than validated human mechanisms in schizophrenia. Importantly, the pathological consequences of oxidative stress are unlikely to be cell-type neutral. Parvalbumin-positive interneurons and oligodendrocyte lineage cells are more vulnerable because of their high metabolic load, limited antioxidant buffering capacity, and lipid/iron-related susceptibility, thereby providing a mechanistic bridge to excitation–inhibition imbalance, myelin abnormalities, and reduced circuit synchrony. Microglial redox–inflammatory signaling may further exacerbate these processes. On the basis of this framework, we argue that the key for future research is not to continue demonstrating the universality of oxidative stress, but to improve the translational efficiency. Biomarker-guided stratification, stage-sensitive study designs, and cell-type-informed therapeutic strategies may therefore provide a more productive path toward redox-targeted interventions in schizophrenia. Full article

The most persistent biomedical challenges of the 21st century are neurodegenerative disorders (NDs), where molecular alterations lead to devastating clinical consequences and progressive neuronal loss. The prevalence of neurodegeneration is continuously rising and becoming the main contributor to chronic disability and mortality. Despite their clinical differences, many conditions share pathogenic processes, including oxidative stress, protein misfolding and aggregation, mitochondrial dysfunction, and neuroinflammation. Instead of functioning independently, these processes cooperate to form a self-reinforcing network that gradually weakens synapses and ultimately leads to neuronal death. This study redefines neurodegeneration as a disorder of system-level failure by emphasizing poor cellular stress integration. In addition to demonstrating how gut microbiome gene networks impact inflammation and amyloid production, new research highlights the relationships between mitochondrial–lysosomal interactions, endoplasmic reticulum stress responses, and transcriptionally driven synaptic vulnerability. A key molecular topic is the interaction and pathogenic convergence of the JAK/STAT, HIF-1α, and Notch signaling pathways. Under ongoing metabolic stress, prolonged stimulation of this triad increases inflammation, hinders the regenerative processes, and maintains pseudo-hypoxic conditions, explaining why single-target treatments have mostly been unsuccessful. This review also explores progress in fluid, digital, and imaging biomarkers that facilitate early diagnosis and patient stratification, and assesses new disease-modifying approaches such as antisense oligonucleotides, immunomodulators, gene therapies, and small-molecular agents. Artificial intelligence is emphasized as an essential tool for integrating multimodal data, drug discovery and predictive modeling. Full article

Hepatic ischemia–reperfusion injury (HIRI) is a major cause of postoperative liver dysfunction and adverse outcomes in hepatectomy, liver transplantation, and hemorrhagic shock. Among the multiple mechanisms implicated in HIRI, mitochondria are recognized as central organelles that integrate metabolic failure, oxidative stress, inflammation, and cell death. During ischemia, interruption of oxygen and nutrient supply impairs oxidative phosphorylation, depletes ATP, disrupts ionic homeostasis, and renders mitochondria highly vulnerable to subsequent injury. Upon reperfusion, reoxygenation triggers excessive reactive oxygen species production, calcium overload, mitochondrial permeability transition pore opening, and release of damage-associated molecular patterns, thereby amplifying hepatocellular injury and sterile inflammatory responses. As a key component of mitochondrial quality control, mitophagy plays a context-dependent role in HIRI. Appropriate activation of mitophagy facilitates the clearance of damaged mitochondria, limits oxidative stress, restrains inflammasome activation, and preserves hepatocellular homeostasis, whereas insufficient or dysregulated mitophagy contributes to mitochondrial accumulation and aggravates liver injury. This review summarizes mitochondrial alterations during the ischemic and reperfusion phases, outlines the major mitophagy pathways involved in HIRI and discusses recent advances in upstream regulation, disease-specific dysregulation, and mitophagy-targeted interventions. A better understanding of the dynamic and biphasic nature of mitophagy in HIRI may provide a stronger theoretical basis for precision liver-protective strategies and future translational therapies. Full article

Background/Objectives: Melatonin is a multifunctional indoleamine with recognized antitumor activity; however, its subtype-specific effects in breast cancer remain incompletely understood. This study aimed to investigate the impact of melatonin on cellular and metabolic processes associated with tumor progression in two human breast cancer cell lines representing distinct molecular subtypes: MCF-7 (luminal A) and MDA-MB-468 (triple-negative). Methods: Breast cancer cells were treated with micromolar concentrations of melatonin, and assays were performed to evaluate cell viability, migration, invasion, mitochondrial status, redox balance, protein expression, and biogenic amine profiles. Results: Melatonin significantly reduced cell viability, migration, and invasion in both cell lines, with more pronounced effects in MCF-7 cells. At the molecular level, melatonin downregulated key metabolic and hypoxia-related proteins, including GAPDH and HIF-1α, while citrate synthase was selectively reduced in MCF-7 cells, indicating suppression of mitochondrial metabolic capacity. This was accompanied by a reduction in mitochondrial status, reflected by decreased MitoGreen staining. Melatonin also induced redox imbalance, as evidenced by increased lipid peroxidation and protein carbonylation, along with subtype-dependent modulation of antioxidant enzymes. In addition, alterations in biogenic amine profiles were observed, suggesting broader metabolic remodeling. Conclusions: Collectively, these findings demonstrate that melatonin exerts subtype-dependent antitumor effects by targeting metabolic, mitochondrial, and redox pathways, supporting further investigation of melatonin as a potential therapeutic adjuvant in breast cancer, while recognizing that the concentrations used in this study exceed physiological circulating levels. Full article

Cognitive frailty, characterized by the coexistence of physical frailty and cognitive impairment, has emerged as a major challenge in aging populations and is closely linked to sarcopenia, neurodegeneration, and chronic inflammation. Increasing evidence suggests that the gut microbiota acts as a central regulator of neuromuscular and neurocognitive aging through the integrated gut–brain–muscle axis. This review highlights how microbial dysbiosis, reduced short-chain fatty acid (SCFA) production, systemic endotoxemia, and altered microbial metabolites contribute to mitochondrial dysfunction, neuroinflammation, anabolic resistance, and impaired neuroplasticity. Key signaling mediators, including SCFAs, bile acids, tryptophan-derived metabolites, cytokines, and myokines such as irisin, brain-derived neurotrophic factor (BDNF), and cathepsin B, orchestrate bidirectional communication among the gut, skeletal muscle, and brain. We further discuss the role of exercise-induced microbiota remodeling and muscle endocrine signaling in promoting mitochondrial biogenesis and cognitive resilience. In addition, emerging translational strategies including probiotics, prebiotics, postbiotics, polyphenol-rich functional foods, marine bioactives, and precision nutrition are explored as potential interventions targeting this axis. Collectively, the gut–brain–muscle axis provides a novel systems biology framework for understanding cognitive frailty and developing integrated therapeutic strategies for healthy longevity. Full article

Biokinetic complexities (plastic sorption, protein binding, and cellular accumulation) may cause large discrepancies between nominal and biologically effective concentrations of test compounds assessed by new approach methods (NAMs). This case study was performed to explore a generally applicable workflow that addresses biokinetic complexities in the context of NAM-based hazard testing for next-generation risk assessment (NGRA). The pesticide tebufenpyrad (TEBU) is a challenging test compound, as it (i) is hydrophobic, (ii) has an intracellular target (mitochondrial respiration), and (iii) is acting at low concentrations (susceptible to biokinetic complexities). In the newly established NeuriTox-M neurotoxicity assay, based on human dopaminergic (LUHMES) neuron cultures, TEBU showed toxic effects at 20 nM. Mass spectrometric analyses of various experimental setups showed that a large fraction (75% to >90%) of TEBU was adsorbed to plastic. This effect was strongly attenuated by albumin in the medium. Cells, cultured on plastic, were considered unsuitable to assess cellular uptake. Therefore, alternatives were explored: when cells were used as suspension cultures (3% v/v) in albumin-containing medium, analysis worked best. Under such conditions, the concentration ratio (cells/medium) of TEBU was around 10. Data from an in vitro distribution (VIVD) model were in good agreement with the measurements. VIVD predicted the unbound medium TEBU concentration (C_u) to be 2–3 orders of magnitude below the nominal concentration and the total cellular concentration to be 10–100-fold above. Standard cell culture assays showed that the medium albumin content indeed altered the TEBU toxicity threshold. More such studies are needed to embed biokinetics information into NGRA. Full article

Mitochondrial dysfunction has been increasingly implicated in the pathobiology of neurodevelopmental conditions, particularly autism and attention-deficit/hyperactivity disorder (ADHD). Because the developing brain is critically dependent on sustained ATP production, impairments in oxidative phosphorylation, mitochondrial dynamics, and redox balance may disrupt neuronal maturation, synaptic development, and neural circuit refinement during sensitive developmental periods. This review examines evidence from postmortem neurochemistry, genomics, magnetic resonance spectroscopy, and biomarker research to characterize mitochondrial impairment across autism and ADHD. Studies in autism report an elevated burden of heteroplasmic mitochondrial DNA (mtDNA) variants, along with alterations in mtDNA copy number, respiratory chain capacity, fission–fusion dynamics, and antioxidant defenses. Postmortem data demonstrate reduced activity of electron transport chain Complexes I, III, and V in the frontal cortex, temporal lobe, and cerebellum. These bioenergetic abnormalities are accompanied by elevated oxidative stress markers alongside mitochondria-mediated immune activation. In vivo neuroimaging corroborates these findings through elevated cerebral lactate and reduced phosphocreatine-to-ATP ratios. Evidence in ADHD is limited, but similarly implicates mitochondrial dysfunction, consistent with the frequent co-occurrence of these conditions and their partially shared architecture. The available literature supports mitochondrial dysfunction as a transdiagnostic biological feature of neurodevelopmental conditions, with relevance to mechanistic biomarker identification and targeted therapeutic development. Full article

Background/Objectives: Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer. Human ccRCCs have increased glycolytic metabolism and decreased mitochondrial oxidative metabolism relative to normal kidneys. Our research using human RCC4 ccRCC cells and a murine model of ccRCC, TRACK (TRAnsgenic model/Cancer/Kidney), in which a triple-mutant (P402A, P564A, N803A) human HIF1α is selectively expressed in proximal tubule cells (PTCs), revealed highly induced ATF4, a stress-responsive transcription factor. We then investigated the role of ATF4 in the metabolic changes in ccRCC. Methods: We performed comprehensive analysis of the ccRCC Cancer Genomics Atlas (TCGA) data. We deleted ATF4 in PTCs of TRACK mice and human RCC4 cells. We conducted genome-wide transcriptomic and untargeted metabolomic studies of cortices of WT and CGERA∆T (TRACK mice with PTC-specific ATF4-knockout (KO)) mice and performed glucose isotopologue tracing in parental and ATF4 KO RCC4 cells. Results: Analysis of TCGA data showed increased mRNAs of enzymes in glycolysis and reduced mRNAs of enzymes in the TCA cycle. Transcriptomic and metabolomic studies demonstrated that ATF4 deletion suppressed glycolysis and enhanced TCA cycle metabolism in CGERA∆T versus WT cortices. Glucose isotopologue tracing showed that ATF4 deletion altered glycolysis pathway metabolite levels and shifted glucose metabolism towards the TCA cycle, evidenced by increased intracellular [¹³C₂]citrate in RCC4-ATF4 KO cells. Using the Seahorse XFe96 analyzer we also showed reduced glycolytic capacity and reserve in RCC4-ATF4 KO cells. Conclusions: Collectively, our results demonstrate that ATF4 regulates glycolysis in ccRCC, supporting ATF4 as a therapeutic target. Full article

Objectives: This study aimed to identify core genes associated with mitochondria-related transcriptomic signatures and evaluate their potential as computational biomarkers, immune characteristics, regulatory mechanisms, and potential therapeutic relevance. Methods: Obesity-related transcriptome datasets were obtained from the GEO database. Differentially expressed genes (DEGs) were intersected with mitochondria-related genes (MRGs) to identify obesity-related MRGs. Functional enrichment, protein–protein interaction (PPI) analysis, CytoHubba, LASSO and random forest algorithms were used to screen core genes. External validation, ROC analysis, immune infiltration analysis, regulatory network construction, candidate drug prediction, and molecular docking were further performed. Results: A total of 527 DEGs and 15 differentially expressed MRGs were identified. Enrichment analysis suggested that these mitochondria-related genes were mainly associated with disrupted mitochondrial energy metabolism, lipid metabolic remodeling, and altered substrate utilization. ECHDC2, FASN, NAT8L, and AASS were identified as core MRGs; these genes are respectively associated with mitochondrial metabolic regulation, de novo fatty acid synthesis, N-acetylaspartate-related mitochondrial metabolism, and lysine degradation. These genes were significantly downregulated in obesity and showed good diagnostic performance. Immune infiltration analysis revealed alterations in the immune microenvironment, and the core genes were negatively correlated with multiple immune cell types. Molecular docking showed that Genistein had the lowest predicted binding free energy with NAT8L (−8.89 kcal/mol), suggesting relatively favorable binding among the tested ligand–target pairs. Conclusions: ECHDC2, FASN, NAT8L, and AASS may serve as candidate computational biomarkers, among which FASN represents a known lipid metabolism-related gene, supporting the biological plausibility of the workflow. Full article

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality, with substantial heterogeneity that is not fully explained by genetic alterations alone. Emerging evidence positions metabolic reprogramming as a central driver of tumor behavior, integrating glycolysis, mitochondrial function, lipid and amino acid metabolism, and autophagy into coordinated networks that extend beyond cancer cells to the tumor microenvironment. Tumor–immune metabolic competition and metabolite-mediated signaling shape immune responses, often promoting immunosuppression and resistance to immunotherapy, particularly in microsatellite-stable (MSS) CRC. Systemic factors, including obesity, insulin resistance, and the diet–microbiota axis, further modulate tumor metabolism and immune function, reinforcing disease progression. Metabolic biomarkers reflecting these multi-level interactions, spanning tumor-intrinsic pathways, immune contexture, and host metabolism, offer promising opportunities for improved patient stratification and therapeutic targeting, although clinical validation remains limited. Current treatments, including chemotherapy, targeted agents, and immune checkpoint inhibitors, are effective in selected subgroups but are constrained by resistance mechanisms. In this review, we propose an integrative immunometabolic framework in which tumor, immune, and systemic metabolic processes co-evolve, defining CRC progression and treatment response. Targeting this interconnected network through combinatorial and metabolism-oriented strategies may enable precision therapies, particularly for immunotherapy-resistant MSS CRC. Full article

Mitochondrial dysfunction and oxidative stress are increasingly recognized as key contributors to the development and progression of retinal degenerative diseases, including age-related macular degeneration and inherited retinal dystrophies. Growing evidence suggests that alterations in mitochondrial function, excessive production of reactive oxygen species, defective mitophagy, and chronic inflammatory responses are closely interconnected processes that contribute to retinal cell damage and degeneration. This review provides an overview of the current understanding of the molecular mechanisms linking mitochondrial dysfunction to retinal degeneration, with particular emphasis on the impact of oxidative stress, mitochondrial quality-control pathways, and inflammatory signaling. Available evidence indicates that mitochondrial DNA damage, impaired bioenergetics, and dysregulated mitochondrial dynamics play a crucial role in the degeneration of photoreceptors and retinal pigment epithelium cells. In turn, oxidative stress further exacerbates mitochondrial impairment, creating a self-sustaining cycle that promotes disease progression. Recent advances have also highlighted the therapeutic potential of targeting mitochondrial pathways. Although several mitochondria-directed strategies have shown encouraging results in experimental models, their translation into clinical practice remains at an early stage. Overall, the available data identify mitochondria as a promising therapeutic target and support the development of precision medicine approaches aimed at preserving retinal function and slowing disease progression in patients with retinal degenerative disorders. Full article

Carbonyl stress, chronic inflammation, and progressive tissue injury accompany type 2 diabetes mellitus (T2DM) and obesity. Yet, the molecular systems that connect these processes with cardiac, vascular and neuronal complications are incompletely defined. This review examines the AGE–RAGE–DIAPH1 axis as a mechanistic link between metabolic dysfunction and diabetic myocardial and neuronal injury, with emphasis on vascular and myocardial remodeling and emerging implications for autonomic neuronal vulnerability. We summarize current evidence on the formation and accumulation of advanced glycation end-products and other RAGE ligands in metabolic disease, DIAPH1’s structural and signaling role as an intracellular effector of RAGE, and the cellular consequences of pathway activation in vascular, neural, and cardiac tissues. Across experimental models, this signaling axis promotes oxidative stress and inflammatory activation, leading to endothelial dysfunction and barrier failure. Subsequent fibrotic remodeling provides a biologically plausible route through which metabolic stress may be translated into persistent organ injury. In the heart, these mechanisms are linked to coronary microvascular dysfunction, altered cardiomyocyte phenotype, calcium handling abnormalities, and myocardial fibrosis. In the autonomic nervous system, limited but emerging data connect RAGE activation to oxidative injury and mitochondrial dysfunction, abnormal neuronal excitability, and structural vulnerability. Direct evidence linking DIAPH1 to autonomic neurons is lacking. We also review biomarker candidates related to this pathway, including circulating AGEs and soluble RAGE isoforms, skin AGE measurements, imaging markers of myocardial remodeling, and autonomic functional measures. Finally, we discuss pharmacological and natural compounds that target AGE formation, ligand accumulation, RAGE signaling, or intracellular protein interactions linked to this axis. Overall, the available evidence supports the AGE–RAGE–DIAPH1 axis as a credible mechanistic concept and a potentially informative translational hypothesis in T2DM. However, the AGE–RAGE component is supported more strongly than DIAPH1-specific involvement in human diabetic myocardial disorder or cardiovascular autonomic neuropathy. The value of DIAPH1 as a biomarker or therapeutic target in these neurocardiac complications remains to be established. Full article

Psychiatric disorders represent a leading cause of disability worldwide and are characterized by substantial biological and therapeutic heterogeneity. Despite significant research efforts, peripheral biomarkers capable of guiding diagnosis, patient stratification, and personalized treatment selection are still lacking. Circulating cell-free DNA (cfDNA) has recently emerged as a promising candidate biomarker, as it may integrate signals of cellular damage, apoptotic activity, and immune activation across multiple tissues. Beyond its role as a marker, cfDNA may also actively contribute to disease processes by functioning as a damage-associated molecular pattern (DAMP), thereby perpetuating inflammatory signaling. The mitochondrial component of cfDNA (cf-mtDNA), which also possesses strong immunostimulatory properties, represents a particularly sensitive indicator of mitochondrial vulnerability to stress. In this context, the present review aims to synthesize the most recent evidence on cfDNA and cf-mtDNA in major psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ). Specifically, we examine their association with psychological stress exposure and childhood trauma, as well as their involvement in inflammation-related pathophysiological mechanisms such as mitochondrial dysfunction, oxidative stress, and hypothalamic–pituitary–adrenal (HPA) axis dysregulation. Available evidence suggests that alterations in cfDNA may be present in subgroups of patients with MDD, BD, and SCZ. However, findings remain heterogeneous and sometimes contradictory, partly due to methodological limitations, including the lack of standardized analytical protocols and insufficient control for potential confounders. Nevertheless, cfDNA holds promise as a tool for inflammation-based patient stratification and for informing personalized therapeutic strategies. Future research directions include the integration of cfDNA within multi-omics frameworks, the analysis of cfDNA methylation profiles to infer tissue of origin, and the exploration of pharmacological strategies aimed at modulating cfDNA as a potential therapeutic target. Full article

Sudden cardiac death (SCD) in athletes often represents the first manifestation of an underlying inherited cardiovascular disorder exposed by adrenergic stress, altered calcium cycling, mechanical loading, and metabolic demand during intense exercise. This review focuses on the molecular architecture that links genotype to arrhythmogenic phenotype in athletes, emphasizing sarcomeric force generation and energetic inefficiency in hypertrophic cardiomyopathy, desmosomal failure and Hippo/Wnt/transforming growth factor-beta (TGF-β) signaling in arrhythmogenic cardiomyopathy, and ion-channel and calcium/calmodulin-dependent protein kinase II (CaMKII)calcium handling abnormalities in inherited channelopathies. This review further examines how exercise-induced physiological remodeling intersects with these pathways through insulin-like growth factor-1 (IGF-1)/phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) signaling, mitochondrial biogenesis, oxidative stress, inflammatory signaling, and epigenetic regulation. Attention is given to the molecular basis of genotype-positive/phenotype-negative states, variable penetrance, and exercise-mediated disease expression. Finally, the integration of molecular biology with genomic data, polygenic risk, and emerging digital phenotyping is discussed to refine mechanism-based risk stratification and identify future therapeutic targets for prevention of SCD in athletes. Full article