Search Results (469)

Parkinson’s disease (PD) is characterized by oxidative stress, mitochondrial dysfunction, and dopaminergic neuron loss, for which effective treatments remain unavailable. Here, we report CL0179, a fungal-derived decahydrofluorene alkaloid with antioxidant-associated neuroprotective properties, and evaluate its effects across cellular and animal PD models. CL0179 exhibited a favorable safety profile and protected SHSY5Y against 6-hydroxydopamine- (6-OHDA), rotenone-, and 1-Methyl-4-phenylpyridinium-iodide (MPP⁺)-induced neurotoxicity by preserving mitochondrial membrane potential and network integrity. Transcriptomic analyses revealed selective restoration of gene-expression programs associated with oxidative phosphorylation, mitochondrial bioenergetics, and stress adaptation disrupted by MPP⁺. CL0179 also enhanced SIRT1 activity under MPP⁺ stress, whereas pharmacological SIRT1 inhibition partially attenuated protection of mitochondrial membrane potential and cell viability. In LRRK2-G2019S astrocytes, CL0179 reduced ROS and α-synuclein accumulation and restored mitochondrial organization, while in human dopaminergic neurons, it attenuated toxin-induced mitochondrial depolarization and preserved neuronal architecture. To overcome the low production of CL0179, we generated the structurally related analogue CL0670. Both compounds crossed the blood–brain barrier and protected mouse primary cortical neurons, while CL0670 improved motor deficits in a 6-OHDA mouse model. Collectively, these compounds promote mitochondrial resilience and stress-adaptive neuroprotection, supporting their potential for PD and related neurodegenerative disorders. Full article

Hepatocellular carcinoma (HCC) is characterized by profound metabolic reprogramming and mitochondrial dysfunction, yet the molecular regulators underlying these alterations remain incompletely understood. AarF domain-containing kinase 1 (ADCK1) is an evolutionarily conserved protein associated with mitochondrial function, but its role in HCC bioenergetics has not been defined. In this study, we investigated the effects of ADCK1 on mitochondrial metabolism using CRISPR/Cas9-mediated ADCK1 knockout in HepG2 and SNU-449 HCC cells. Mitochondrial respiration, glycolytic activity, ATP production, lactate generation, mitochondrial membrane potential, and superoxide production were assessed following ADCK1 KO. ADCK1 KO resulted in marked reductions in basal and maximal mitochondrial respiration, ATP-linked respiration, glycolytic activity, intracellular ATP, and lactate production in both HCC cell models. ADCK1 KO also reduced mitochondrial membrane potential in a clone-dependent manner. Despite these profound bioenergetic defects, mitochondrial superoxide production was not consistently altered across the knockout clones. These findings indicate that ADCK1 supports both oxidative phosphorylation and glycolytic metabolism and is required for maintenance of bioenergetic homeostasis in HCC cells. Collectively, our results identify ADCK1 as a previously unrecognized regulator of HCC mitochondrial metabolism. Full article

Thyroid hormone physiology has traditionally been understood through the hypothalamic–pituitary–thyroid (HPT) axis and the genomic actions of triiodothyronine (T3). However, advances in thyroid hormone biology have expanded this classical paradigm, demonstrating that thyroid hormone signaling is regulated through a coordinated network involving tissue-specific deiodination, specialized membrane transporters, genomic and non-genomic signaling pathways, and mitochondrial regulation of cellular bioenergetics. Among the iodothyronine metabolites generated through thyroid hormone metabolism, 3,5-diiodothyronine (3,5-T₂) has emerged as one of the most extensively investigated because of its reported ability to rapidly influence mitochondrial respiration, oxidative metabolism, and energy expenditure. Experimental studies suggest that 3,5-T₂ enhances mitochondrial respiration, fatty acid oxidation, oxidative phosphorylation, and metabolic efficiency, particularly in metabolically active tissues such as liver and skeletal muscle. These findings have generated considerable interest in the potential role of 3,5-T₂ in metabolic disorders characterized by mitochondrial dysfunction, including metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, and insulin resistance. However, important translational challenges remain. Most available data derive from animal studies using pharmacologic doses, while the endogenous physiology of 3,5-T₂ in humans, its molecular targets, tissue-specific regulation, and long-term endocrine effects remain incompletely understood. In addition, evidence of hypothalamic–pituitary–thyroid axis suppression following exogenous 3,5-T₂ administration and limitations in accurately measuring circulating 3,5-T₂ continue to complicate clinical translation. This review critically evaluates the emerging biology of 3,5-diiodothyronine, integrating current evidence regarding its biosynthesis, mechanisms of thyroid hormone signaling, mitochondrial actions, metabolic effects, translational challenges, and future research priorities. By synthesizing findings from primary experimental studies and emerging translational investigations, this review places 3,5-T₂ within the broader framework of contemporary thyroid hormone biology while highlighting key knowledge gaps that must be addressed before its physiological and therapeutic significance can be fully established. Full article

The co-occurrence of liver cirrhosis (LC) and heart failure (HF) poses considerable clinical challenges, yet the cellular and molecular determinants of this comorbidity remain poorly characterized. To address this, we developed an integrative multi-omics pipeline encompassing GWAS meta-analysis, gsMap-based spatial transcriptomic projection, GeneEnrich functional annotation, single-cell atlas construction, seismicGWAS and ECLIPSER cell-type scoring, eCAVIAR and fastenloc colocalization, hdWGCNA network inference, scTenifoldKnk in silico gene perturbation, and GCTA-COJO fine-mapping. Quality-controlled meta-analysis yielded 12,347,758 and 9,256,862 variant-level associations for LC and HF, respectively. Spatial projection confirmed preferential enrichment of disease signals within embryonic hepatic and cardiac compartments. Pathway analyses disclosed that LC-linked loci were concentrated in lipid metabolic programs, whereas HF-linked loci implicated mitochondrial bioenergetics and lysosomal degradation. At the cellular level, endothelial cells emerged as the dominant HF-associated population. Convergent evidence from five orthogonal algorithms pinpointed CRIM1 as the sole robustly supported shared gene, selectively enriched in HF endothelial cells; virtual perturbation further identified LCP1 and PTPRC as downstream regulatory nodes. Fine-mapping of the chromosome 2 locus harboring rs12476437 revealed multiple statistically independent signals in the vicinity of CRIM1. Collectively, these findings computationally prioritize the endothelial–CRIM1 axis as a previously unappreciated candidate mechanistic bridge between LC and HF requiring experimental validation. Full article

Astrocyte senescence is a recognized feature of brain aging, but its impact on neuronal mitochondrial homeostasis remains poorly defined, particularly in human cells. Here we show that doxorubicin-induced senescence disrupts mitochondrial function in primary human astrocytes and compromises their capacity to sustain neuronal bioenergetics. Senescent astrocytes accumulated a denser population of smaller, ultrastructurally damaged mitochondria together with increased levels of fission, fusion and biogenesis-associated proteins. Despite this apparent expansion of the mitochondrial compartment, these cells displayed reduced mitochondrial membrane potential, intracellular ATP and cellular metabolic activity, indicating accumulation of a functionally impaired mitochondrial population. Senescence also remodeled the extracellular mitochondrial compartment: conditioned medium from senescent astrocytes contained fewer mitochondrial particles with lower membrane potential and reduced ATP. Functionally, conditioned medium from control astrocytes increased TOMM20 and PGC-1α levels in human postmitotic neurons, whereas medium from senescent astrocytes failed to elicit this response and instead promoted hydrogen peroxide accumulation, ATP depletion and reduced cellular metabolic activity in the absence of overt cytotoxicity. Neurons acquired an astrocyte-derived MitoTracker signal from both conditions. Our data indicate that factors released by senescent human astrocytes are sufficient to induce neuronal mitochondrial and redox dysfunction. Full article

Barth syndrome (BTHS) is a rare, X-linked genetic disorder caused by mutations in the enzyme TAFAZZIN (TAZ), resulting in insufficient cardiolipin (CL) remodeling and mitochondrial dysfunction. While BTHS respiratory distress and breathing difficulties are commonly reported, the precise role of intrinsic respiratory tissue vulnerabilities has only recently begun to be appreciated. Historically, BTHS respiratory distress is frequently attributed to secondary consequences like cardiomyopathy or generalized skeletal myopathy, leaving the intrinsic vulnerability of vital respiratory muscles poorly understood. Using a patient-tailored point mutant knock-in mouse model (Taz^PM) harboring a stable but enzymatically deficient Taz^D75H protein, we investigated the autonomous physiological and metabolic responses in the diaphragm and lungs. Contrary to the paradigm that respiratory muscles are unaffected, Taz^PM diaphragms exhibit structurally abnormal mitochondria and undergo a survival-critical, bifurcated compensatory remodeling response to prevent fatal respiratory failure under severe bioenergetic stress. The Taz^PM adaptive mechanism is orchestrated by chronic activation of the mitochondrial Integrated Stress Response (ISR) via the Gcn2/eIF2α signaling pathway. This stress pathway halts global translation to conserve cellular ATP at the expense of reduced NAD+ levels, while selectively upregulating defensive mitokines and metabolic sirtuins and structural muscle remodeling. Furthermore, the Taz^PM diaphragm transitions into a highly specialized, slow-twitch motor system that is expected to reduce the energy cost per contraction. Concurrently, despite Taz^PM lungs exhibiting structurally abnormal mitochondria, they resist generalized mitochondrial collapse despite ADP reduction, executing tissue-specific metabolic reprogramming and localized biochemical adaptations to sustain respiratory homeostasis. Full article

Age-related skeletal muscle wasting, clinically expressed as sarcopenia and frailty, significantly limits the efficacy of physical rehabilitation due to an underlying cellular bioenergetic decline, mitochondrial dysfunction, and chronic inflammaging. This narrative review synthesizes current physiological and clinical evidence evaluating mitochondria- targeted nutraceuticals as targeted metabolic adjuvants to physical exercise in older adults. Comprehensive literature searches were executed across PubMed, Web of Science, and Scopus following SANRA guidelines and the SPIDER framework to evaluate functional and bioenergetic outcomes in geriatric cohorts. The findings demonstrate that target-specific biofactors directly impact mitochondrial restrictions: ubiquinol and NAD⁺ precursors restore electron transport chain efficiency and biogenesis; urolithin A upregulates mitophagy to prevent the cytosolic extrusion of pro-inflammatory mitochondrial DNA, while creatine monohydrate and omega-3 polyunsaturated fatty acids selectively restore downstream myofibrillar anabolic pathways. When translated to specialized clinical settings, including post-fracture orthopedic immobilization, chronic pain syndromes managed, and post-ICU-acquired weakness, these bioenergetic substrates safely mitigate tissue proteolysis and enhance recovery kinetics. In conclusion, structurally integrating biomarker-driven nutritional rehabilitation pathways with tailored exercise protocols provides the precise pro-anabolic microenvironment necessary to overcome anabolic resistance, ultimately shortening recovery timelines and maximizing functional independence in the aging population. Full article

Alzheimer’s disease (AD) is increasingly recognized as a disorder involving profound mitochondrial dysfunction. Although photobiomodulation (PBM) has shown neuroprotective efficacy in experimental AD models, whether restoration of mitochondrial architecture is mechanistically required for these effects remains unknown. Here, we investigated the role of mitochondrial network remodeling in PBM-mediated neuroprotection in primary mouse hippocampal neurons exposed to amyloid-β (Aβ). Neurons were treated for 24 h with oligomeric Aβ_1–42 and irradiated with 808 nm PBM (100 mW/cm², 30 J/cm²). Mitochondrial morphology was quantified using three-dimensional confocal microscopy and computational network analysis. Aβ exposure induced severe mitochondrial fragmentation and swelling, reflected by increased mitochondrial count and sphericity together with reduced mitochondrial volume, surface area, branch length, and network connectivity. These structural alterations were accompanied by elevated reactive oxygen species production, adenosine triphosphate depletion, membrane depolarization, and reduced neuronal viability. PBM significantly reversed these abnormalities, restoring mitochondrial network integrity and partially normalizing cellular bioenergetics and redox homeostasis. To determine whether mitochondrial dynamics contributes to PBM-induced effects, neurons in another experiment were pre-treated with the dynamin-related protein-1 (DRP-1) mitochondrial division inhibitor-1 (Mdivi-1). The physiological and morphological profiles of the Aβ + PBM + Mdivi-1 and Aβ + Mdivi-1 groups were found to be largely indistinguishable in this case, revealing that PBM failed to restore mitochondrial connectivity, cellular bioenergetics, or viability of neurons in the partially blocked fission–fusion machinery. These findings demonstrate that mitochondrial dynamics is essential for PBM-mediated neuroprotection and identify restoration of mitochondrial network integrity as a crucial mechanism linking PBM to improved neuronal bioenergetics, redox balance, and survival in AD. Full article

Mitochondria are increasingly recognized as dynamic regulators of cancer-cell adaptation, immune function, and therapeutic response. Beyond their canonical role in energy production, mitochondrial metabolism, dynamics, quality control, and stress signaling influence tumor-cell survival and the capacity of immune effector cells to sustain antitumor activity within the tumor microenvironment. In this narrative review, we examine mitochondrial fitness as a multidimensional functional property encompassing bioenergetic capacity, metabolic flexibility, redox homeostasis, mitochondrial quality control, and adaptation to cellular and therapeutic stress. We propose the mitochondrial functional immune checkpoint as a conceptual framework linking mitochondrial fitness in malignant and immune cells to tumor–immune interactions and immunotherapy response. We discuss how mitochondrial metabolic plasticity, mitochondrial stress and mtDNA signaling, reactive oxygen species, mitochondrial dynamics, and intercellular mitochondrial transfer contribute to immune escape and treatment resistance. We further examine the relevance of mitochondrial fitness to immune checkpoint blockade, CAR-T-cell therapy, and T-cell-redirecting bispecific antibodies, with particular attention to hematological malignancies, including acute myeloid leukemia and multiple myeloma, while incorporating selected evidence from solid tumors to highlight shared mitochondrial mechanisms and their broader oncologic relevance. Finally, we discuss emerging strategies for mitochondrial targeting and functional mitochondrial profiling and their potential integration with established molecular and measurable residual disease assessments. Current evidence supports mitochondrial biology as a complementary dimension of precision oncology, although important challenges remain regarding context dependence, biomarker standardization, therapeutic selectivity, and preservation of immune-cell fitness. Prospective studies are needed to determine whether functional mitochondrial profiling can improve patient stratification and guide rational therapeutic combinations that selectively exploit tumor mitochondrial vulnerabilities while preserving effective antitumor immunity. Full article

Autophagy plays a central role in cellular homeostasis and metabolic adaptation, and its dysregulation has been implicated in metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). This study investigated the biological effects of a chemically characterised multi-component nutraceutical formulation using an integrated in vitro gut–liver–muscle axis model under lipotoxic and inflammatory conditions induced by free fatty acids (FFAs) and lipopolysaccharide (LPS). The principal bioactive constituents were quantified in both the individual extracts and the final formulation before biological testing. Caco-2, HepG2, and C2C12 cells were sequentially exposed to conditioned media to reproduce inter-organ metabolic interactions. The Supplement preserved intestinal barrier integrity by maintaining transepithelial electrical resistance and tight junction protein expression. In HepG2 cells, it preserved telomerase levels, improved markers of cellular metabolic adaptation, modulated AMPK/mTOR and SIRT1 signalling, and promoted autophagy-related responses, including increased LC3-II/I ratio, reduced p62 accumulation, and preservation of lysosomal markers. In skeletal muscle cells, exposure to conditioned medium derived from formulation-treated compartments was associated with improved cellular bioenergetics, reduced oxidative stress and inflammatory mediators, and enhanced ATP and glycogen levels under exercise-like conditions. Overall, these findings provide preliminary evidence that the chemically characterised formulation modulates interconnected pathways involved in intestinal barrier function, hepatic autophagy-related processes, and skeletal muscle metabolic adaptation under the experimental conditions employed. Full article

Cyanobacteria are promising platforms for bioenergy, carbon sequestration, and bioproduct synthesis, but their photosynthetic efficiency is limited by suboptimal light utilization, electron transport constraints, and environmental stress. Titanium dioxide nanoparticles (n-TiO₂) have emerged as powerful photocatalytic materials that can enhance light absorption, modulate electron transport, and influence the redox balance in biological systems. This review advances the concept of photocatalytic-biological coupling, in which n-TiO₂ functions as artificial light amplifiers that augment cyanobacterial photosynthesis. Current evidence on the physicochemical properties of n-TiO₂, their interactions with cyanobacterial cells, and their effects on photosystems, electron transport chains, and downstream metabolic processes is examined. Particular emphasis is placed on the integration of photophysical and biological mechanisms, including reactive oxygen species (ROS)-mediated signaling, proton motive force (PMF) enhancement, and adenosine triphosphate (ATP) synthesis. Emerging approaches, including nano–bio interface engineering, environmental biotechnology applications, and artificial intelligence-guided optimization, are highlighted. By bridging photophysics, cellular bioenergetics, and computational design within a unified mechanistic framework, this review establishes the scientific foundation needed to translate photocatalytic–biological coupling into scalable and biotechnologically deployable nano-enabled photosynthetic systems. Full article

Background/Objectives: Mitochondrial Complex V (Complex V [CX-V], or ATP synthase) is the terminal enzyme of oxidative phosphorylation and is responsible for the majority of cellular ATP production. An increasing body of evidence suggests that CX-V dysfunction may contribute to mitochondrial impairment observed in neurodegenerative disease. This review evaluated current research on the structure, regulation, and function of CX-V, examined the consequences of CX-V dysfunction, and assessed its proposed role in neurodegenerative disorders. Methods: A comprehensive review of the published literature was carried out, with emphasis on primary research investigating CX-V structure and function, inherited CX-V disorders, and experimental evidence linking CX-V dysfunction to neurodegenerative disease. The reviewed studies used a range of experimental approaches, including structural biology, biochemical studies, patient-derived cellular models, animal models and post-mortem human tissue. Results: Current evidence demonstrates that disruption of CX-V impairs ATP production, alters mitochondrial membrane potential, and oxidative phosphorylation, and that pathogenic variants cause primary mitochondrial disease. Across Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis/frontotemporal dementia, glaucoma and inherited optic neuropathies, alterations in CX-V activity, regulation and structural integrity are consistently associated with mitochondrial dysfunction. Direct evidence supporting CX-V as a primary driver of neurodegeneration remains very limited, with many observations originating from broader studies of general mitochondrial dysfunction. Conclusions: CX-V dysfunction represents a recurring feature of mitochondrial impairment across a variety of neurodegenerative disorders and may exacerbate neuronal vulnerability by disrupting cellular bioenergetics. Current evidence indicates that CX-V may serve as a common downstream target of multiple pathological pathways rather than acting as a primary pathological factor. Future studies require direct assessment of CX-V activity in clinically relevant human models and patient tissues to determine its contribution to disease progression and examine its potential as a therapeutic target. Full article

Background/Objectives: Exposure to lead (Pb) is a serious public health concern for which there is no safe level. The aim of this study was to investigate the toxicity of Pb to undifferentiated (uSH-SY5Y) and differentiated (dSH-SY5Y) human neuroblastoma cells and to evaluate gene transcription in response to sub-lethal lead exposure. Methods: Pb was applied to uSH-SY5Y and dSH-SY5Y cells across a concentration range of 0–5 mM for 4, 6, and 24 h, and cell viability was assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase assays. Results: Pb induced a significant concentration- and exposure-dependent reduction in cell viability. Pb significantly impacted cellular bioenergetics and reduced ATP production in a concentration- and exposure duration-dependent manner, triggering elevated levels of deleterious reactive oxygen species. Transcriptomic profiling in dSH-SY5Y cells after a sub-lethal 24 h exposure to 1.25 mM Pb revealed 757 upregulated and 2206 downregulated genes. From Gene Ontology and KEGG pathway enrichment analysis, biological processes were predominantly associated with immune and inflammatory processes, including cytokine-mediated signalling. Upregulated differentially expressed genes (DEGs) included those for PI3K/Akt and cytokine signalling, and downregulated DEGs included genes linked to spinocerebellar ataxia, mitophagy, cytokine receptor interaction and cellular metabolism. Protein–protein interaction analysis identified six key hub-upregulated genes with a primarily inflammatory focus (CD44, CXCR4, PTGS2, IL1β, TNF, MMP9) and one downregulated gene (CD4) as potential regulators of Pb-induced cellular responses. Disease association analyses revealed links to chemical carcinogenesis and neurodegenerative diseases. Conclusions: Collectively, these findings provide molecular insights into Pb-induced neurotoxicity and highlight a network of genes that converge on neurological and inflammatory pathways, which are candidates for further mechanistic investigation and possible therapeutic targeting following Pb poisoning. Full article

Traditional bioenergetic paradigms historically relied on classical equilibrium thermodynamics to calculate mitochondrial kinetics, often overlooking the non-equilibrium processes dictated by complex structural architecture. Recent discoveries fundamentally challenge these outdated views by demonstrating that the inner mitochondrial membrane is strictly segregated into distinct functional domains, where individual cristae operate as autonomous, ultra-confined nanocompartments, where the transport of metabolites and protons is tightly controlled by ultrastructure-assisted electric and entropic effects. Compartmentalization prevents proton dissipation, allows for the rapid generation of a localized proton motive force optimized for efficient ATP synthesis and provides robust functional redundancy against localized membrane damage. Furthermore, recognizing cristae as isolated microspaces resolves the long-standing paradox of mitochondrial nicotinamide adenine dinucleotide transhydrogenase (TH). We describe a multi-stage transport pipeline—the TH–isocitrate dehydrogenase axis—wherein matrix-generated reducing equivalents are exported into the cytoplasm via an irreversible isocitrate/α-ketoglutarate loop. This universal pipeline continuously supplies uncommitted NADPH for biosynthesis, systemic antioxidant defense and detoxification. We also highlight the role of compartmentalization in ATP transport and utilization processes. Consequently, disruptions to cristae compartmentalization emerge as primary pathogenic drivers in ischemic, neurodegenerative, and cardiovascular diseases. Full article

Cardiac fibrosis is a hallmark of pathological cardiac remodeling, characterized by fibroblast activation, excessive extracellular matrix deposition, and myocardial hypertrophy, ultimately leading to cardiac dysfunction. Aging exacerbates these processes through metabolic stress and impaired mitochondrial bioenergetics. Here, we investigated the anti-fibrotic effects of metformin and the role of fatty acid β-oxidation (FAO) in regulating cardiac fibroblast differentiation. Metformin significantly attenuated transforming growth factor-β (TGF-β)-induced cardiac fibroblast activation and the associated senescence-like phenotype. These effects were accompanied by enhanced FAO and increased mitochondrial oxygen consumption rate (OCR), indicating improved mitochondrial function. Importantly, inhibition of carnitine palmitoyltransferase-1 (CPT1) with etomoxir largely abolished the beneficial effects of metformin on mitochondrial respiration, fibroblast activation, and cellular senescence, demonstrating a critical role for FAO. Mechanistically, metformin increased CPT1 activity and acetyl-CoA levels while reducing malonyl-CoA accumulation, thereby promoting mitochondrial fatty acid utilization. These findings were corroborated in aged Apoe^−/− mice, where metformin reduced the expression of cardiac fibroblast differentiation markers and enhanced FAO-associated markers. Collectively, our findings demonstrate that metformin suppresses cardiac fibroblast differentiation and senescence by preserving mitochondrial bioenergetics through FAO-dependent mechanisms, revealing a metabolic basis for its anti-fibrotic actions and supporting its therapeutic potential in age-related cardiovascular disease. Full article