Search Results (234)

Oocyte competency is a crucial determinant of fertilisation success and the initial development of embryos in assisted reproductive technologies. The metabolic and biochemical environment of the ovarian follicle is crucial for determining oocyte developmental potential, alongside genetic integrity. The follicular microenvironment includes a complex network of signalling chemicals that regulate mitochondrial activity, steroidogenesis, oxidative balance, and cellular energy metabolism. Recently, metabolic hormones originating from adipose tissue and skeletal muscle, namely, adipokines and myokines, have received considerable focus as crucial regulators of ovarian physiology. Adiponectin, irisin, and the recently identified hormone asprosin have emerged as crucial metabolic regulators influencing granulosa cell activity, mitochondrial bioenergetics, insulin signalling pathways, and redox homeostasis inside the follicular niche. Adiponectin mostly provides metabolic protection by activating AMP-activated protein kinase (AMPK) and improving insulin sensitivity, which in turn enhances mitochondrial efficiency and steroidogenic function in granulosa cells. Irisin, derived from the breakdown of fibronectin type III domain-containing protein 5 (FNDC5), aids the developing oocyte by facilitating mitochondrial biogenesis, augmenting oxidative phosphorylation, and altering cellular defence mechanisms against oxidative stress. Conversely, asprosin has been associated with glucogenic signalling, metabolic stress, and probable mitochondrial malfunction, suggesting a possible relationship between systemic metabolic problems and negative reproductive consequences. Clinical and experimental research indicate that the levels of these metabolic regulators in follicular fluid may correlate with ovarian response, oocyte quality, fertilisation rates, and embryo development during in vitro fertilisation cycles. This review consolidates current molecular, cellular, and clinical information, clarifying the pathways by which adipokines and myokines influence follicular metabolism and impact oocyte competency. Understanding the metabolic connections between systemic endocrine signals and the follicular milieu may provide novel indicators for reproductive prognosis and provide new treatment targets to improve assisted reproduction outcomes. Full article

Background: Metabolic syndrome (MetS) and alcohol-related liver disease (ALD) are increasingly recognized as interconnected disorders linked by shared mechanisms of lifestyle-driven metabolic reprogramming. Alterations in systemic and hepatic metabolic pathways—including insulin signaling, lipid metabolism, mitochondrial bioenergetics, and redox homeostasis—reduce hepatic resilience to alcohol exposure and accelerate liver disease progression. Objective: This narrative review aims to integrate clinical, epidemiological, and mechanistic evidence published over the past two decades to examine how modifiable lifestyle factors contribute to metabolic reprogramming linking metabolic syndrome and alcohol-related liver disease with prioritization of high-level clinical evidence (cohort studies, meta-analyses, and guidelines). Key Findings: Modifiable lifestyle exposures such as alcohol consumption, cigarette smoking, unhealthy dietary patterns, and physical inactivity converge on common metabolically mediated pathways, including insulin resistance, dysregulated lipid metabolism and lipotoxicity, mitochondrial dysfunction, oxidative stress, chronic low-grade inflammation, and gut–liver axis perturbations. These processes are reflected in altered metabolite profiles involving lipid species, bile acids, tricarboxylic acid cycle intermediates, and microbiota-derived metabolites, shaping a metabolic–hepatic continuum. Among these, alcohol consumption and metabolic dysfunction show the strongest and most consistent associations with liver disease progression, with evidence supporting synergistic rather than additive effects. Conclusions: The coexistence of metabolic dysfunction and alcohol exposure is consistently associated with synergistic worsening of liver-related outcomes, including fibrosis progression, cirrhosis, and hepatocellular carcinoma. Recognition of metabolic alcohol-related liver disease (MetALD) underscores the need for integrated lifestyle-based strategies targeting alcohol consumption, smoking cessation, dietary quality, and physical activity to modulate shared metabolic and inflammatory pathways. A metabolically informed, systems-level approach may improve risk stratification, prevention, and management across the metabolic–hepatic continuum. Full article

Saline–alkaline water constitutes a vital strategic non-traditional fishery resource in China, characterized by high pH values, elevated carbonate alkalinity, and complex ionic compositions. These extreme environmental conditions impose significant stress on aquatic animals, mainly by inducing ionic toxicity and disrupting acid–base regulatory mechanisms. Such disruptions subsequently lead to osmotic imbalance, metabolic dysregulation, and immunosuppression, thus restricting the survival and growth of aquatic species in aquaculture systems. Consequently, the sustainable development of the saline–alkaline aquaculture is imperative for enhancing production efficiency and promoting the utilization of marginal land and water resources. This review comprehensively summarizes the current status of saline–alkaline aquaculture and highlights the stress-inducing impacts of salinity, alkalinity, and specific ionic ratios on teleost fishes and crustaceans. It further explores key adaptive mechanisms, including osmoregulatory and ionoregulatory strategies, bioenergetic trade-offs related to oxygen consumption and ammonia excretion, coordinated antioxidant and innate immune responses, as well as recent findings from multi-omics research. This review aims to offer a scientific foundation for the selection and breeding of saline–alkaline-tolerant strains, the precise regulation of aquaculture water environments, and the development of ecological aquaculture models in saline–alkaline regions, thereby facilitating the sustainable utilization of saline–alkaline land and water resources. Full article

Chronic kidney disease (CKD) involves uremic toxin-driven tubular injury and systemic vascular dysfunction, in which mitochondrial impairment and apoptotic cell loss contribute to progressive tissue deterioration. Accordingly, a targeted EV platform is required to enable efficient miRNA delivery to the toxin-stressed tubular–endothelial compartment. Based on our previous study showing that melatonin restores miR-4516 levels under CKD-related stress, we directly loaded miR-4516 into engineered extracellular vesicles (EVs) to evaluate its effects on mitochondrial function and cell survival. Here, we engineered EVs with a G3-C12/RGD surface modification and established a miR-4516 loading strategy to enhance delivery to kidney proximal tubule cells and vascular endothelial cells. miR-4516 loading increased EV-associated miR-4516 levels without major changes in particle size distribution, and EV identity was supported by CD9 and CD81 expression. Confocal microscopy and flow cytometry demonstrated increased cellular uptake of miR-4516-loaded G3-C12/RGD-EVs compared with control EVs in TH1 proximal tubule cells and HUVECs. Under indoxyl sulfate stress, engineered EV treatment restored intracellular miR-4516 and improved mitochondrial function, as indicated by recovery of respiratory Complex I and Complex IV activities and improved Seahorse bioenergetic parameters (OCR/ECAR, basal and maximal respiration, ATP-linked respiration, and spare respiratory capacity). Annexin V staining further indicated reduced toxin-induced apoptosis. In an adenine diet-induced CKD mouse model, intravenous administration of miR-4516-loaded G3-C12/RGD-EVs improved urinary albumin-to-creatinine ratio (UACR), blood urea nitrogen (BUN), and serum creatinine. These findings indicate that miR-4516-loaded, targeting-engineered EVs may mitigate uremic toxin-associated mitochondrial dysfunction and renal impairment in CKD. Full article

Cardiovascular disease remains the leading global cause of mortality, largely due to the limited regenerative capacity of adult human myocardium. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer a scalable platform for cardiac repair and disease modeling; however, their persistent metabolic immaturity—characterized by reliance on glycolysis, reduced oxidative phosphorylation (OXPHOS), and structurally underdeveloped mitochondria—limits functional integration and long-term therapeutic efficacy. Recent advances indicate that targeted metabolic reprogramming can enhance mitochondrial biogenesis, increase ATP production, and improve stress resilience in iPSC-CMs. This review examines the complementary integration of CRISPR-based metabolic engineering and extracellular vesicle (EV)-mediated metabolic modulation as a systems-level strategy for cardiac maturation. We discuss CRISPR activation, interference, and epigenome-editing approaches targeting regulators such as PGC-1α, TFAM, and PPARs to promote stable enhancement of mitochondrial networks and respiratory capacity. In parallel, engineered EVs delivering miRNAs, metabolic enzymes, and redox modulators provide non-genomic mechanisms to optimize bioenergetic function and mitigate oxidative stress. By synthesizing mechanistic insights, quantitative bioenergetic metrics, and translational considerations, we propose CRISPR-EV synergy as a precision framework for durable metabolic maturation of iPSC-CMs, with implications for regenerative therapy, pharmacologic screening, and myocardial repair. Full article

Glaucoma is a multifaceted optic neuropathy, characterized by the progressive loss of retinal ganglion cells. This damage frequently continues even after intraocular pressure (IOP) has been effectively lowered. This resistance to conventional IOP-lowering therapy underscores the critical role of interacting IOP-independent mechanisms; specifically metabolic failure and systemic mitochondrial dysfunction have emerged as key parallel drivers. This review analyzes the paradigm shift from a pressure-centric model to a bioenergetic one, focusing on mitochondrial function, peripheral blood mononuclear cell (PBMC) biomarkers, and oxygen consumption dynamics. We synthesize evidence demonstrating that glaucoma patients exhibit a metabolic vulnerability, characterized by lower PBMC oxygen consumption rates and depleted systemic nicotinamide adenine dinucleotide levels relative to healthy individuals. Furthermore, compromised systemic respiratory performance correlates with more rapid worsening of visual fields and structural thinning, independent of IOP status. Moreover, we delineate the role of Complex I defects, SARM1-mediated axonal degeneration, and proteomic alterations, which indicate defective mitophagy. These findings establish systemic metabolic profiling as a valuable supplementary tool for assessing patient risk and support the clinical translation of neuroprotective therapies targeting mitochondrial bioenergetics, specifically nicotinamide, pyruvate, coenzyme Q₁₀, and metformin. Full article

The maturation of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) remains a major translational bottleneck in regenerative cardiac medicine, as current differentiation platforms yield electrophysiologically and metabolically immature phenotypes. This review explores emerging strategies to engineer “smart” biomaterial interfaces that actively instruct iPSC-CM maturation through synergistic biophysical and metabolic reprogramming. By integrating nanotopographical patterning, mechanoelectric coupling, and tunable substrate stiffness with metabolic interventions such as mitochondrial substrate optimization and fatty acid oxidation induction, the literature reveals consistent links between cell–matrix crosstalk, sarcomeric organization, calcium handling, and oxidative metabolism. Recent advances in bioactive scaffolds and extracellular vesicle (EV)-functionalized hydrogels are highlighted as platforms capable of approximating key features of the myocardium’s native electromechanical and bioenergetic environment. Across two- and three-dimensional culture systems, this review identifies recurring maturation patterns, persistent gaps in metric standardization and long-term phenotype stability, and ongoing limitations related to scalability and translational implementation. Collectively, the findings synthesized here indicate that convergence between biomaterial engineering and metabolic programming represents a critical design principle for advancing iPSC-CMs toward functionally mature, clinically relevant phenotypes. This integrated approach enhances the fidelity of iPSC-CMs for disease modeling, drug screening, and regenerative cardiac therapies. Full article

The co-occurrence of ammonia nitrogen and hypoxia represents a physiologically taxing synergistic challenge for benthic bivalves—as it forces a conflict between the high energy demand for detoxification and the limited energy supply under low oxygen, yet the tissue-specific strategies underlying their resilience remain poorly understood. This study investigated the physiological and transcriptomic responses of the razor clam Sinonovacula constricta to ammonia (AG), hypoxia (HG), and their combination (HAG) over 96 h. Transcriptomic profiling revealed that the gill and hepatopancreas employ distinct, organ-coordinated adaptive strategies rather than a uniform systemic response. The gill prioritized respiratory homeostasis by fine-tuning oxygen sensing: transcriptional suppression of hypoxia-inducible factor 1-α (HIF-1α) (to limit glycolytic acidosis) was followed by a chronic induction of HIF-2α, alongside the specific upregulation of the mitochondrial respiratory gene cytochrome c oxidase-6b (COX-6b). In contrast, the hepatopancreas executed a critical metabolic trade-off centered on arginine metabolism. Under combined stress, arginine flux was redirected toward the urea cycle via a robust upregulation of arginase (ARG) for detoxification, while nitric oxide synthase (NOS) was concurrently suppressed. This reciprocal regulation suggests a strategy to prioritize ammonia clearance and energy conservation at the expense of immune signaling. These findings elucidate how S. constricta navigates the bioenergetic conflict between detoxification and oxygen limitation, providing molecular targets for breeding stress-resistant aquaculture strains. Full article

Energy homeostasis arises from a complex interplay between gut-derived hormones, the central nervous system, and pancreatic function. Beyond the classical incretin axis, a broad spectrum of gut peptides acts in concert to coordinate appetite regulation, nutrient sensing, gastric motility, and systemic bioenergetic balance. Perturbation of this network contributes to metabolic disorders such as obesity, type 2 diabetes, and cachexia, underscoring its pivotal role in physiological and pathological energy regulation. This review provides an integrated analysis of the mechanisms through which gut–brain–pancreas communication maintains metabolic homeostasis, with particular attention to the dynamic cross-talk between peripheral endocrine signals and central regulatory circuits. Alterations in these pathways are examined in relation to their impact on energy expenditure and substrate utilisation, alongside recent translational efforts exploiting multi-receptor peptide agonism and combinatorial hormonal modulation to restore metabolic equilibrium. Emerging therapeutic approaches increasingly aim to engage multiple bioenergetic pathways simultaneously, supported by advances in peptide engineering and molecular design. By conceptualising metabolic regulation as a coordinated network rather than a linear hormonal cascade, this article delineates a physiological and translational framework for next-generation interventions targeting bioenergetic dysfunction in human disease. Full article

Metabolomic studies in COPD reveal systemic metabolic perturbations, yet sex is often treated as a covariate rather than a biological driver. We aimed to identify plasma metabolites differentiating COPD from controls and to define sex-specific metabolic signatures in both groups. Methods: In this controlled observational study (BIOMEPOC cohort), untargeted plasma metabolomics was performed by LC-MS/MS. Differential abundance was tested across four contrasts (COPD vs. controls; men vs. women within controls; men vs. women within COPD; sex-by-disease interaction) with a false discovery rate (FDR) correction. Because smoking history differed between COPD and controls, a post hoc ever-smokers analysis was conducted. Results: COPD differed from controls in nine metabolites (all decreased): DL-stachydrine, 3-methyl-L-histidine, fructose, pipecolinic and nipecotic acids, 5-nitro-o-toluidine, conjugated linoleic acid, aminoadipate, and creatinine. This pattern is compatible with metabolic depletion, remodeling, and/or altered flux across multiple compartments rather than simple substrate deficiency, spanning muscle-related pools, amino acid handling, carbohydrate-associated metabolism, and exposome-linked inputs. In ever-smokers, results were directionally consistent, with five metabolites remaining nominally significant. Among controls, five metabolites were higher in men after FDR correction (PABA, cis-4-hydroxy-D-proline, N-acetylasparagine, deoxycarnitine, and creatinine), consistent with physiological sex dimorphism in energy pathways, connective-tissue remodeling, and diet/microbiome-related metabolism. Within COPD, six metabolites differed by sex after FDR correction, defining three axes: creatine energy buffering (men: higher GAA/creatinine, lower creatine), purine/urate handling (men: higher urate), and conjugated bile acids (men: higher GCDCA), implicating muscle bioenergetics, redox/inflammatory tone, and gut–liver crosstalk. Conclusions: Plasma metabolomics identifies a pattern compatible with systemic remodeling in COPD and sex-associated divergences in creatine, purine/urate, and bile-acid pathways, supporting a sex-influenced view of systemic COPD heterogeneity and highlighting targets for mechanistic validation. Full article

Quantifying oxidative, glycolytic, and phosphagen energy system contributions during exercise is challenging due to their simultaneous activation and reliance on indirect estimation. This narrative review critically examines the methodological foundations, assumptions, and practical implications of current approaches used to estimate energy system contributions during continuous and intermittent exercise, with the aim of clarifying how these methods shape the interpretation of bioenergetic responses. Oxidative contribution, primarily estimated through oxygen uptake (VO₂) integration, typically exceeds (~75–88%) in continuous efforts longer than 6 min and can reach values above ~87% when exercise duration allows full development of VO₂ kinetics, particularly in trained young adult cohorts. In contrast, supramaximal efforts shorter than 30–90 s involve markedly lower oxidative contribution, commonly below ~50% and as low as ~8–19%. Glycolytic contribution is inferred from net blood lactate concentration accumulation and increases with exercise intensity, ranging from ~3–5% in longer severe-intensity efforts to values up to ~60% during brief maximal tasks lasting 15–30 s. Phosphagen contribution is estimated using the fast component of post-exercise VO₂ recovery or theoretical phosphocreatine breakdown models, and can reach ~39–48% in maximal efforts lasting 10–15 s, while declining to values below ~10% in prolonged exercise. Each method is shaped by exercise duration, intensity, structural format, and physiological assumptions, contributing to methodological heterogeneity and limiting direct comparability between studies. Advances in portable gas analyzers, near-infrared spectroscopy, and biosensing technologies have improved temporal resolution and ecological validity. To enhance the accuracy and practical application of energy system profiling, standardized and integrative frameworks are urgently required. Full article

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome driven by systemic inflammation, persistent oxidative stress, endothelial dysfunction, and impaired mitochondrial bioenergetics. Despite recent therapeutic advances, the management of these specific pathophysiological mechanisms remains a challenge. Polyphenols, bioactive compounds found in plants, have emerged as potential modulators of these pathways. Objective: This review critically summarizes the pathophysiological and molecular evidence supporting the role of polyphenols—specifically phenolic acids, flavonoids, and lignans—in attenuating key pathways implicated in the progression of HFpEF, while also addressing the current limitations in clinical translation. Results: Preclinical evidence indicates that polyphenols regulate cellular homeostasis by activating the Keap1/Nrf2 antioxidant axis and AMPK/SIRT1 metabolic pathways, while inhibiting NF-κB-mediated pro-inflammatory signals and TGF-β fibrotic pathways. These molecular actions collectively preserve endothelial function via PI3K/Akt/eNOS, reduce interstitial fibrosis, and improve myocardial metabolic efficiency. Furthermore, the modulation of gut microbiota amplifies these systemic effects, particularly in obesity-related phenotypes. However, direct clinical application is currently hindered by low bioavailability and a scarcity of randomized trials specifically in HFpEF populations. Polyphenols represent a promising and biologically plausible nutritional therapeutic axis for the multidimensional management of HFpEF. While the molecular rationale is strong, future research should focus on improving bioavailability and conducting high-quality clinical trials to validate efficacy as an adjuvant therapy. Full article

Anderson–Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene, resulting in deficient α-galactosidase A activity and progressive accumulation of globotriaosylceramide (Gb3) and its derivative lyso-Gb3 within lysosomes. Beyond substrate storage, FD involves a complex interplay of molecular, metabolic, and inflammatory disturbances that collectively drive multisystemic damage. It seems that Gb3 accumulation impairs autophagic flux, promotes mitochondrial dysfunction, and triggers endoplasmic reticulum stress, leading to oxidative imbalance and bioenergetic failure. Concurrently, activation of innate immune pathways, particularly the TLR4/NF-κB axis, induces pro-inflammatory cytokine release and endothelial dysfunction, while complement activation and adaptive immune responses contribute to chronic inflammation and fibrosis. These mechanisms define a sustained state of “metaflammation,” linking lysosomal dysfunction to systemic inflammation. Understanding this molecular cross-talk provides a rationale for identifying novel biomarkers and designing therapies that go beyond enzymatic correction, including chaperone therapy, substrate reduction, and gene-based or anti-inflammatory approaches. A deeper comprehension of these interconnected patterns may guide the development of precision medicine strategies aimed at improving long-term outcomes in Fabry disease. Full article

Mitochondrial dysfunction lies at the core of numerous cardiac pathologies, yet restoring mitochondrial health remains a therapeutic frontier. In recent years, extracellular vesicles (EVs) have emerged as nature’s delivery nanocarriers, capable of transporting a wide array of biomolecules, including mitochondrial-associated microRNAs (mito-miRs). These miRNAs regulate bioenergetics, redox homeostasis, and apoptotic signaling—making them prime candidates for non-cellular mitochondrial therapy. This review explores the evolving landscape of mitochondrial miRNA encapsulation within EVs, focusing on their potential to restore mitochondrial transcriptional and metabolic programs governing ATP synthesis and redox balance, enhance cellular energy output, and mitigate oxidative stress. We integrate insights from stem cell biology, RNA epigenetics, systems cardiology, and bioengineering, offering a unifying framework for therapeutic applications across ischemic heart disease, heart failure, and chemotherapy-induced cardiomyopathy. An integrative narrative synthesis of recent peer-reviewed literature was performed across major biomedical databases, prioritizing mechanistic studies linking EV-mediated mito-miR delivery to cardiomyocyte mitochondrial function. By harmonizing multi-omic signaling, vesicle engineering, and mitochondrial medicine, this review seeks to guide future research toward targeted, customizable, and scalable bioenergetic interventions—unlocking a next-generation path for cardiovascular regeneration. Full article

This review synthesizes research on mechanisms of microplastic-induced mitochondrial damage, focusing on oxidative stress and inflammation to address the mechanistic pathways linking microplastic exposure to mitochondrial dysfunction and cellular toxicity. Analysis of diverse in vitro and in vivo studies across aquatic, terrestrial, and mammalian systems was conducted, emphasizing molecular, cellular, and functional mitochondrial parameters. Findings reveal consistent microplastic-induced reactive oxygen species generation, disrupting mitochondrial membrane potential and bioenergetics, with smaller and aged particles exerting greater toxicity. Inflammatory signalling via NF-κB, the NLRP3 inflammasome, and immune cell necroptosis is closely associated with oxidative stress, forming a feedback loop that exacerbates mitochondrial impairment. Molecular mechanisms implicate endocytic uptake pathways, mitochondrial calcium dysregulation, and apoptosis-related cascades, though causal validation remains limited. The interplay between oxidative stress and inflammation emerges as a central driver of mitochondrial damage across models. These integrated insights highlight the critical influence of microplastic physicochemical properties and biological context on mitochondrial and inflammatory responses. The findings inform future mechanistic research and underscore the need for standardized models to assess microplastic toxicity, advancing understanding of environmental and human health risks associated with microplastic pollution. Full article