Search Results (301)

Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse event triggered by antiresorptive and/or anti-angiogenic agents, characterized by bone destruction, sequestrum formation, and refractory mucosal defects. Effective mucosal healing can be a critical factor for MRONJ prevention and treatment. While endoplasmic reticulum stress (ER stress) has been implicated in tissue repair, its role in MRONJ-associated mucosal healing impairment remains undefined. This study investigated the effects of the anti-angiogenic drug sunitinib on oral mucosal healing and its underlying mechanisms. A mouse model of palatal mucosal defects was established, RNA-seq, transmission electron microscopy, and morphological analyses were used to assess how sunitinib affects ER function during mucosal repair. Using human oral keratinocytes (HOKs), we further elucidated the subcellular mechanisms through which sunitinib influences cell proliferation, migration, cell cycle progression, tight junctions, and apoptosis via techniques such as qPCR, Western blotting, immunofluorescence, and flow cytometry. Our findings demonstrated that sunitinib might induce significant alterations in the morphology of the ER and mitochondria. Both in vivo and in vitro experiments revealed that sunitinib persistently activates the GRP78 (BIP)/PERK/ATF4/CHOP axis in HOKs. This sustained ER stress can inhibit keratinocytes migration and proliferation, disrupt tight junctions, and trigger the intrinsic mitochondrial apoptotic pathway, ultimately leading to impaired oral mucosal healing and barrier dysfunction. Critically, pharmacological inhibition of ER stress was shown to restore keratinocytes’ function and promote effective mucosal healing. These results indicated that targeting sunitinib-induced persistent ER stress might represent a promising therapeutic strategy to prevent and treat oral mucosal toxicity associated with this drug. Full article

Lead (Pb) disrupts mitochondrial function, but its impact on the mitochondrial dynamics and biogenesis during early brain development remains insufficiently understood. This study aimed to investigate the effects of pre- and neonatal Pb exposure on the processes involved in mitochondrial network formation in the brains of rat offspring, simulating environmental exposure. We quantified mRNA expression (qRT-PCR) and protein levels (ELISA) of key mitochondrial fusion (Mfn1, Mfn2, Opa1), fission (Drp1, Fis1) regulators, as well as biogenesis markers (PGC-1α, TFAM, NRF1) in the hippocampus, forebrain cortex, and cerebellum of rats exposed to Pb. Mitochondrial ultrastructure was evaluated using transmission electron microscopy (TEM), and the expression of mitochondrial electron transport chain (ETC) genes was analysed (qRT-PCR). Furthermore, to examine the involvement of the cGAS–STING pathway in Pb-induced neuroinflammation, we measured the expression of ISGs (qRT-PCR), TBK1 phosphorylation (Western blot), and 2′,3′-cGAMP synthesis (ELISA). Our results showed that Pb exposure markedly reduced PGC-1α and region-specific NRF1 levels, broadly supressed fusion proteins (Mfn1, Mfn2, Opa1), increased Fis1, and depleted Drp1. ETC gene expression (mtNd1, mtCyb and mtCo1) were upregulated in a brain-structure-dependent manner. These molecular changes were accompanied by pronounced mitochondrial morphological abnormalities. Despite upregulation of Mx1, Ifi44, and Sting1, along with synthesis of 2′3′-cGAMP, TBK1 activation was not detected. All these findings demonstrate that early-life Pb exposure, even low-dose, disrupts mitochondrial biogenesis and the fusion–fission machinery, thus impairs brain energy homeostasis, and implicates mitochondria as central mediators of Pb-induced neuroinflammation and neurodevelopmental toxicity. Full article

Plant-derived extracellular vesicles (PEVs) have emerged as a promising area of research in biotechnology with enormous potential in drug delivery, skincare, and functional foods. Currently, PEVs are obtained primarily from fresh and dried materials through soaking and extraction; however, little is known about the differences in their contents. Using Portulaca oleracea L. as the research object, this study firstly employed a method that combined differential and ultracentrifugation with membrane filtration to separate and purify exosome-like nanoparticles from dried material (D-PELNs) and fresh material (F-PELNs). Then, multi-omics analysis compared the small-molecule metabolites, lipid profiles, and protein expression patterns. Both D-PELNs and F-PELNs showed typical cup-shaped morphology, with mean particle sizes of 139 nm and 186 nm, and mean zeta potentials of −16.015 ± 0.335 mV and −6.29 ± 0.19 mV, respectively. Both types contained diverse small-molecule metabolites. Among them, terpenoids (e.g., caesaldekarin e) were more abundant in F-PELNs, whereas carboxylic acids and their derivatives (e.g., citric acid) were predominantly found in D-PELNs. Both types had abundant lipids. D-PELNs exhibited greater lipid diversity than F-PELNs, with notable enrichment in phosphatidylcholine (18.48%) and ceramide (17.02%). F-PELNs mainly consisted of functional neutral lipids, such as monoglycerides and triglycerides. Proteins involved in plant morphogenesis and secondary-metabolite biosynthesis were also identified. Proteins from both Portulaca oleracea L.-derived exosome-like nanoparticles (PELNs) were localized to intracellular structures, including the cytoplasm and mitochondria of the cells. D-PELNs had a higher protein content related to carbon metabolism, whereas F-PELNs were more enriched in proteins related to secondary metabolite synthesis. In summary, D-PELNs and F-PELNs were successfully isolated and characterized, and their compositions were analyzed and compared using multi-omics approaches. These findings identify the specific chemical components of PELNs and offer new insights for comparing the compositional differences between exosome-like nanoparticles derived from dried and fresh plant states. Full article

Mitochondrial dysfunction is a pivotal contributor to neurodegeneration. Neurons heavily rely on mitochondrial oxidative metabolism and therefore need highly efficient quality control mechanisms, including proteostasis, mitochondrial biogenesis, fusion–fission dynamics, and mitophagy, to sustain bioenergetics and synaptic function. With aging, deterioration of mitochondrial quality control pathways leads to impaired oxidative phosphorylation, excessive reactive oxygen species generation, calcium imbalance, and defective clearance of damaged organelles, ultimately compromising neuronal viability. Pathological protein aggregates, such as α-synuclein in Parkinson’s disease, β-amyloid and tau in Alzheimer’s disease, and misfolded superoxide dismutase 1 and transactive response DNA-binding protein 43 in amyotrophic lateral sclerosis, further aggravate mitochondrial stress, establishing self-perpetuating cycles of neurotoxicity. Such mitochondrial defects underscore mitochondria as a convergent pathogenic hub and a promising therapeutic target for neuroprotection. Intermediate filaments (IFs), traditionally viewed as passive structural elements, have recently gained attention for their roles in cytoplasmic organization, mitochondrial positioning, and energy regulation. Emerging evidence indicates that IF–mitochondria interactions critically influence organelle morphology and function in neurons. This review highlights the multifaceted involvement of mitochondrial dysfunction and IF dynamics in neurodegeneration, emphasizing their potential as targets for novel therapeutic strategies. Full article

Background/Objectives: Mitophagy, the selective removal of damaged mitochondria, plays a pivotal role in regulating cardiac hypertrophy and fibrosis under pressure overload. Targeting mitophagy may help mitigate adverse cardiac remodeling. This preclinical study examined the effects of cafestol, a coffee-derived diterpene, on pressure overload-induced cardiac hypertrophy and fibrosis in mice, with emphasis on mitophagy modulation and mitochondrial ultrastructure. Methods: Male normotensive mice underwent transverse aortic constriction (TAC) and received cafestol at 2, 10, or 50 mg/kg/day via oral gavage for 28 days. Cardiac function was assessed by echocardiography. Histological and molecular analyses quantified fibrosis, inflammation, and apoptosis. Protein expression of CD68, CTGF, DDR2, α-SMA, CD44, galectin-3 (Gal3), collagen I, GAPDH, Bcl-2, Bax, cleaved caspase-3, GRP78, p-ERK/ERK, ATF4, p-mTOR/mTOR, and p62 was evaluated. Transmission electron microscopy (TEM) was used to assess autophagosome formation and mitochondrial morphology. Results: TAC induced significant cardiac hypertrophy and fibrosis, accompanied by elevated expression of fibrotic (CTGF, DDR2, α-SMA, collagen I), inflammatory (CD68, CD44, Gal3), apoptotic (Bax, cleaved caspase-3), and endoplasmic reticulum stress markers (GRP78, ATF4). TEM revealed increased autophagosome accumulation and disrupted mitochondrial architecture. Cafestol treatment reduced collagen deposition, immune cell infiltration, and apoptotic signaling; enhanced Bcl-2 expression; and restored p62 levels. TEM findings demonstrated decreased autophagosome burden and preserved mitochondrial structure, consistent with improved mitophagic flux and mitochondrial homeostasis. Conclusions: Cafestol mitigated pressure overload-induced cardiac remodeling in mice by modulating mitophagy, suppressing fibrotic and inflammatory responses, and preserving mitochondrial integrity. These findings support further investigation of cafestol’s mechanisms and safety profile in preclinical models of cardiovascular disease. Full article

Chronic alcohol misuse is the leading cause of non-ischemic dilated cardiomyopathy, and the molecular mechanisms underlying the development of alcohol-associated cardiomyopathy (ACM), particularly regarding sex-specific susceptibility and mitochondrial contributions, are not fully known. In this study, we utilized a preclinical model of chronic + binge ethanol consumption to investigate sex differences in disease severity and mitochondrial function. Male and female C57BL/6J mice were fed ethanol or control liquid diets for 30 days, with 2 binge episodes on days 10 and 30. Cardiac morphology was assessed via echocardiography and cardiac function via left ventricular pressure–volume catheterization. Mitochondrial function was evaluated ex vivo using Seahorse XF analysis, ATP luminescence, and AmplexTM Red fluorescence in isolated ventricular mitochondria. Ethanol feeding induced significant cardiac dysfunction and increased transcriptional expression of inflammatory and fibrotic markers in males, while these effects were not seen in females. Despite these sex-specific cardiac effects, mitochondrial respiration, ATP production, collagen protein expression, and oxidative stress were not significantly altered following alcohol exposure in either sex. Further investigation is warranted to assess the potential role of ovarian hormones in this female cardioprotection against chronic + binge ethanol. Full article

Aging is a major risk factor for cardiovascular disease, driving progressive structural and functional decline of the myocardium. Mitochondria, the primary source of ATP through oxidative phosphorylation, are essential for cardiac contractility, calcium homeostasis, and redox balance. In the aging heart, mitochondria show morphological alterations including cristae disorganization, swelling, and fragmentation, along with reduced OXPHOS efficiency. These defects increase proton leak, lower ATP production, and elevate reactive oxygen species (ROS), causing oxidative damage. Concurrent disruptions in mitochondrial fusion and fission further impair turnover and quality control, exacerbating mitochondrial dysfunction and cardiac decline. Serum response factor (SRF) signaling, a crucial regulator of cytoskeletal and metabolic gene expression, plays a key role in modulating mitochondrial function during cardiac aging. Dysregulation of SRF impairs mitochondrial adaptability, contributing to dysfunction. Additionally, reduced levels of nicotinamide adenine dinucleotide (NAD⁺) hinder sirtuin-dependent deacetylation, further compromising mitochondrial efficiency and stress resilience. These cumulative defects activate regulated cell death pathways, leading to cardiomyocyte loss, fibrosis, and impaired diastolic function. Mitochondrial dysfunction therefore serves as both a driver and amplifier of cardiac aging, accelerating the transition toward heart failure. This narrative review aims to provide a comprehensive overview of mitochondrial remodeling in the aging myocardium, examining the mechanistic links between mitochondrial dysfunction and myocardial injury. We also discuss emerging therapeutic strategies targeting mitochondrial bioenergetics and quality control as promising approaches to preserve cardiac function and extend cardiovascular health span in the aging population. Full article

TRIC-A is an intracellular cation channel enriched in excitable tissues that is recently identified as a key modulator of sarcoplasmic reticulum (SR) Ca²⁺ homeostasis through direct interaction with type 2 ryanodine receptors (RyR₂). Given the intimate anatomical and functional coupling between the SR and mitochondria, we investigated whether TRIC-A contributes to SR–mitochondrial crosstalk under cardiac stress conditions. Using a transverse aortic constriction (TAC) model, we found that TRIC-A^−/− mice developed more severe cardiac hypertrophy, underwent maladaptive remodeling, and activated apoptotic pathways compared with wild-type littermates. At the cellular level, TRIC-A-deficient cardiomyocytes were more susceptible to H₂O₂-induced mitochondrial injury and displayed abnormal mitochondrial morphology. Live-cell imaging revealed exaggerated mitochondrial Ca²⁺ uptake during caffeine stimulation and increased propensity for store-overload-induced Ca²⁺ release (SOICR). Complementary studies in HEK293 cells expressing RyR₂ demonstrated that exogenous TRIC-A expression attenuates RyR₂-mediated mitochondrial Ca²⁺ overload, preserves respiratory function, and suppresses superoxide generation. Together, these findings identify TRIC-A as a critical regulator of SR–mitochondrial Ca²⁺ signaling. By constraining mitochondrial Ca²⁺ influx and limiting oxidative stress, TRIC-A safeguards cardiomyocytes against SOICR-driven injury and confers protection against pressure overload-induced cardiac dysfunction. Full article

Type 2 diabetes mellitus (T2DM) is a chronic disease that has become a serious health problem worldwide. Moreover, increased systemic and cerebrovascular inflammation is one of the major pathophysiological features of T2DM, and a growing body of evidence emphasizes T2DM with memory and executive function decline. Bioactive sphingolipids regulate a cell’s survival, inflammatory response, as well as glucose and insulin signaling/metabolism. Moreover, current research on the role of sphingosine kinases (SPHKs) and sphingosine-1-phosphate receptors (S1PRs) in T2DM is not fully understood, and the results obtained often differ. The aim of the present study was to evaluate the effect of metformin (anti-diabetic agent, MET) on the brain’s sphingosine-1-phosphate-related signaling and ultrastructure in diabetic mice. Our results revealed elevated mRNA levels of genes encoding sphingosine kinase 2 (SPHK2) and sphingosine-1-phosphate receptor 3 (S1PR3), which was accompanied by downregulation of sphingosine-1-phosphate receptor 1 (S1PR1) in the hippocampus of diabetic mice. Simultaneously, upregulation of genes encoding pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) was observed. Administration of MET significantly reversed changes in mRNA levels in the hippocampus and reduced Sphk2, Il6, and Tnf, with concomitant upregulation of S1pr1 gene expression. Ultrastructural analysis of diabetic mice hippocampus revealed morphological alterations in neurons, neuropil, and capillaries that were manifested as mitochondria swelling, blurred synaptic structure, and thickened basal membrane of capillaries. The use of MET partially reversed those changes. Our research emphasizes the important role of insulin sensitivity modulation by metformin in the regulation of SPHKs and S1PRs and inflammatory gene expression in a murine model of T2DM. Full article

Skeletal muscle, constituting 40–50% of total body mass, is vital for mobility, posture, and systemic homeostasis. Muscle contraction heavily relies on ATP, primarily generated by mitochondrial oxidative phosphorylation. Mitochondria play a key role in decoding intracellular calcium signals. The endocannabinoid system (ECS), including CB₁ receptors (CB₁Rs), broadly influences physiological processes and, in muscles, regulates functions like energy metabolism, development, and repair. While plasma membrane CB₁Rs (pCB₁Rs) are well-established, a distinct mitochondrial CB₁R (mtCB₁R) population also exists in muscles, influencing mitochondrial oxidative activity and quality control. We investigated the role of mtCB₁Rs in skeletal muscle physiology using a novel systemic mitochondrial CB₁ deletion murine model. Our in vivo studies showed no changes in motor function, coordination, or grip strength in mtCB₁ knockout mice. However, in vitro force measurements revealed significantly reduced specific force in both fast-twitch (EDL) and slow-twitch (SOL) muscles following mtCB₁R ablation. Interestingly, knockout EDL muscles exhibited hypertrophy, suggesting a compensatory response to reduced force quality. Electron microscopy revealed significant mitochondrial morphological abnormalities, including enlargement and irregular shapes, correlating with these functional deficits. High-resolution respirometry further demonstrated impaired mitochondrial respiration, with reduced oxidative phosphorylation and electron transport system capacities in knockout mitochondria. Crucially, mitochondrial membrane potential dissipated faster in mtCB₁ knockout muscle fibers, whilst mitochondrial calcium levels were higher at rest. These findings collectively establish that mtCB₁Rs are critical for maintaining mitochondrial health and function, directly impacting muscle energy production and contractile performance. Our results provide new insights into ECS-mediated regulation of skeletal muscle function and open therapeutic opportunities for muscle disorders and aging. Full article

Plant-insect mutualisms often drive the evolution of adaptive morphological and physiological traits, enabling ecological specialization and diversification. Fig trees (Ficus spp., Moraceae) and their pollinating wasps (Agaonidae) are engaged in a brood-site pollination mutualism that exemplifies such adaptive specializations. This study investigates the morphological and ecological roles of maculae, characterized as distinct-pigmented regions on the fig surface, in the mutualistic interaction between Ficus citrifolia and fig wasps. Through morphological analyses using light and electron microscopy, we demonstrated that maculae concentrate numerous stomata and exhibit secretory activity. This activity is evidenced by the exudation of a sugary-like solution and by the presence of epidermal and subepidermal cells with features consistent with sugar- and terpene-secreting cells, such as abundant starch reserves, numerous mitochondria, plastids containing osmiophilic droplets, a Golgi complex with dilated cisternae, oil bodies, and extensive endoplasmic reticulum. Histochemical tests confirmed a terpenic-sugary secretion in the macula cells. We demonstrated that non-pollinating fig wasps avoid ovipositing through macular regions. This behavior may reflect a selective pressure to prevent structural damage to maculae caused by ovipositor insertion, thus preserving their functional integrity. Temperature measurements revealed that figs are up to 10% cooler on average than the ambient air. Therefore, our findings suggest that fig maculae are multifunctional structures, simultaneously performing the roles of extrafloral nectaries, gas exchange, and thermal regulation, which are crucial for maintaining suitable internal conditions for wasp larval development. These results provide novel insights into previously underexplored plant adaptations supporting specialized brood-site pollination mutualisms. Full article

Metastasis is the primary cause of cancer-related deaths. As a multi-step process, tumor metastasis encompasses several key aspects. Tumor cells first traverse the basement membrane and subsequently invade the surrounding vascular or lymphatic systems, ultimately leading to secondary colonization. Throughout the progression of metastasis, tumor cells can overcome selective pressures and transition between different cellular states, depending on the diverse functions of mitochondria. Mitochondria not only function as energy generators but also co-evolve with host cells, acting as critical signaling hubs in various biological pathways. Under sustained stress conditions such as nutrient deficiency, cellular stress, and the reprogramming of gene expression, alterations in mitochondrial morphology and function can prevent cell death and facilitate the targeted transformation of oncogenes, tumor progression, and the emergence of invasive cell phenotypes. The multifaceted roles of mitochondria enable tumor cells to evade unfavorable environments and establish colonies in more conducive sites. In summary, this review consolidates the complex interactions between mitochondria and cancer while elucidating their significant role in cancer metastasis and therapeutic responses. Full article

Mitochondria play a pivotal role in fungal growth, development, and metabolic regulation, yet their significance has often been overlooked in traditional breeding programs. Auricularia heimuer, the second most widely cultivated edible fungus in China, has attracted increasing attention due to its nutritional and health-promoting properties, underscoring the urgent need for the development of functional cultivars and the elucidation of mitochondrial regulatory mechanisms. In this study, we constructed isonuclear alloplasmic strains with identical nuclear genotypes but distinct mitochondrial backgrounds. Comparative analyses of mycelial growth, fruiting body morphology, and nutritional composition were conducted, alongside transcriptomic profiling. The results showed no significant morphological differences on sawdust-based medium; however, on PDA medium, the strains exhibited notable differences in growth rate, melanin content, β-glucan levels, iron ion concentration, and amino acid content. Transcriptomic analysis identified 3385 differentially expressed genes (DEGs), which were enriched in pathways related to lysine biosynthesis, purine metabolism, DNA replication, and repair. Key DEGs involved in lysine biosynthesis were found to encode aminoadipate reductase (AAR) and saccharine dehydrogenase (SDH), with AAR localized in the cytoplasm and potentially regulating lysine synthesis through its enzymatic activity. This study highlights the critical influence of mitochondrial genes on the metabolic composition and transcriptional landscape of A. heimuer, providing a theoretical foundation for genetic improvement and the development of functional fungal cultivars. Full article

Alzheimer’s disease, a neurodegenerative brain disorder leading to the progressive decline in cognitive functions, is the most common type of dementia. The main risk factor for its development is aging. Recent studies indicate that cellular senescence mechanisms are among the major factors in a heterogeneous aging process. Cellular senescence is characterized by a permanent proliferative arrest. Many factors might initiate senescence, for example, damage of DNA, shortening of telomeres, dysfunction of mitochondria, and oncogene activation. These processes lead to alterations in the morphology and function of senescent cells. Research is still ongoing to identify one universal marker that could detect senescent cells and distinguish them from other non-proliferating cells. Those cells are involved in age-related pathologies through many heterogeneous processes, including secretion of pro-inflammatory senescence-associated secretory phenotype factors, which affect the brain differently. Alzheimer’s disease is an example of a neurodegenerative condition connected to cellular senescence. Senescent cells have been demonstrated to accumulate near Aβ plaques and neurofibrillary tangles. In this review, the multifactorial connection between Alzheimer’s disease and cellular senescence is discussed, including topics such as senescence of astrocytes, defective mitochondria, dysregulation of cellular autophagy, and the role of senescent microglia. Full article

Photobiomodulation (PBM) consists of applying low-level laser light to biological tissues, leading to modulation of cellular functions. PBM has recently gained much attention in the field of regenerative dentistry thanks to its powerful effect on tissue repair and regeneration. Dental pulp mesenchymal stem/stromal cells (DP-MSCs) represent the ideal targets in regenerative dentistry due to their ability to stimulate the regeneration of mineralized and soft tissues and the paracrine factors that they produce. Although there have been several studies evaluating the influence of PBM on DP-MSCs’ regenerative capacity, the results are conflicting, and there are few studies on the influence of PBM on the paracrine factors released by DP-MSCs. Therefore, the aim of this study was to investigate the effect of PBM, using different energy doses of laser irradiation, on the osteogenic capacity of DP-MSCs, focusing on changes in gene expression, mineralizing ability, and release of pro-osteogenic factors. DP-MSCs were irradiated in vitro and differentiated into an osteogenic phenotype. A cell viability assay, alizarin red staining, and TEM analysis were carried out to evaluate the effect of PBM on cell activity, morphology, and mineralization ability. The expression of the main osteogenesis-related markers Runx2, Col1A1, ALP, and BMP was measured to evaluate the influence of PBM on the ability of DP-MSCs to differentiate toward an osteogenic phenotype. The release of IL-6 and IL-8, which are mainly involved in bone remodeling processes, was investigated in the cell medium following PBM irradiation. The results showed a high level of cell viability, suggesting a lack of phototoxicity under the tested conditions. Furthermore, PBM had a significant effect on mineral deposition, IL-6 and IL-8 release, and expression of osteogenic markers. TEM analysis showed intracellular modifications linked mainly to mitochondria, the endoplasmic reticulum, and autophagic vesicles after PBM treatment. These findings demonstrated that the impact of PBM on the osteogenic potential of DP-MSCs is energy dose-dependent, supporting its potential as an effective strategy in regenerative dentistry, particularly for enhancing bone remodeling. Full article