Search Results (8,837)

Mitochondria are increasingly recognized as multifunctional organelles that integrate metabolic, redox, immune, and cell fate signaling, thereby maintaining cellular and tissue homeostasis under physiological conditions. Beyond their classical role in ATP production, mitochondria act as central regulatory hubs coordinating adaptive responses to metabolic demands and environmental stress. These functions are sustained through tightly regulated quality control mechanisms, including mitochondrial biogenesis, dynamic fusion–fission remodeling, redox signaling, and selective removal of damaged organelles via mitophagy. Disruption of these processes compromises cellular resilience and contributes to disease initiation and progression. This review summarizes and critically evaluates current evidence on mitochondrial function in health and its dysregulation in pathological conditions, with a particular focus on rheumatoid arthritis (RA), ischemic stroke (IS), and autism spectrum disorder (ASD). Despite their distinct clinical manifestations, these disorders share convergent mitochondrial abnormalities, including metabolic reprogramming toward glycolysis, excessive or persistent reactive oxygen species production, impaired mitophagy, mitochondrial DNA-driven innate immune activation, and hypoxia-related stress. In RA, mitochondrial dysfunction sustains chronic inflammation and joint destruction; in IS, acute mitochondrial failure and reperfusion-associated oxidative stress drive neuronal injury; and in ASD, mitochondrial metabolic inflexibility and defective quality control contribute to chronic low-grade inflammation and neurodevelopmental vulnerability. A variety of methods for the assessment of mitochondrial function are available to study these pathological conditions. Collectively, these findings position mitochondrial dysfunction as a unifying pathogenic mechanism linking inflammatory, neurodegenerative, and neurodevelopmental processes. Targeting mitochondrial metabolism, redox balance, and quality control pathways therefore represents a promising cross-disease therapeutic strategy. Full article

Background: Glioblastoma (GBM) exhibits marked cellular heterogeneity and resistance to therapy. Calcium (Ca²⁺) signaling at endoplasmic reticulum (ER)–mitochondria contact sites has emerged as a key regulator of mitochondrial function and cell fate; however, its lineage-specific role and therapeutic relevance in GBM remain unclear. Methods: ITPR1 expression was analyzed using single-cell and bulk RNA sequencing (RNA-seq) datasets and validated by immunohistochemistry and survival analyses. Functional studies were conducted using genetic silencing or CRISPR-mediated activation of ITPR1, combined with DRP1 knockdown, Ca²⁺ imaging, transmission electron microscopy, co-immunoprecipitation, mitochondrial fractionation, and mitochondrial functional assays. Therapeutic efficacy was evaluated in orthotopic GBM xenograft models treated with 2-aminoethoxydiphenyl borate (2-APB), temozolomide (TMZ), or their combination. Results: ITPR1 was enriched in mesenchymal-like malignant cell states and associated with higher tumor grade, recurrence, and poor prognosis. ITPR1 knockdown suppressed GBM cell proliferation and tumor growth while promoting intrinsic apoptosis. Mechanistically, loss of ITPR1 impaired ER-to-mitochondria Ca²⁺ transfer, disrupted ER–mitochondria contacts, and altered mitochondrial ultrastructure. This was accompanied by reduced DRP1 Ser616 phosphorylation and mitochondrial recruitment, as well as decreased autophagy and mitophagy activity. Consequently, ITPR1 knockdown led to mitochondrial depolarization, increased mitochondrial reactive oxygen species (ROS) accumulation, and activation of mitochondria-dependent apoptosis. Conversely, DRP1 knockdown attenuated the mitochondrial and pro-survival effects induced by ITPR1 overexpression. In vivo, combined treatment with 2-APB and TMZ resulted in greater tumor suppression and prolonged survival compared with either treatment alone, accompanied by increased apoptosis and reduced proliferation in tumor tissues. Conclusions: ITPR1 promotes GBM progression by sustaining ER–mitochondria Ca²⁺ coupling and DRP1-dependent mitochondrial quality control, thereby maintaining mitochondrial homeostasis and cell survival. Targeting inositol 1,4,5-trisphosphate receptor (IP₃R)-mediated Ca²⁺ signaling with 2-APB enhances the therapeutic efficacy of TMZ, suggesting that ITPR1-centered Ca²⁺ signaling may represent a potential therapeutic vulnerability in aggressive GBM. Full article

Ceramides are central bioactive sphingolipids that regulate diverse cellular processes, including membrane organization, energy metabolism, and stress signaling. Emerging evidence has implicated that ceramide dysregulation is associated with the onset and progression of heart failure. This review introduces the understanding of ceramide metabolism, focusing on its biosynthesis, and functional roles in cardiomyocytes. In addition, the contribution of systemic ceramides derived from circulating lipoproteins and peripheral tissues to cardiovascular risk is also discussed. In parallel, it is highlighted that cardiomyocyte-intrinsic ceramide synthesis plays physiological and pathological roles in the heart. Particularly, excessive ceramide accumulation is detrimental for cardiac function, through multiple mechanisms, such as lipotoxic effects, mitochondrial impairment, inflammation, and cell death. The current review discusses the potential diagnostic and therapeutic strategies targeting ceramide metabolism, as well as the open questions about ceramide association with heart disease. Full article

T-2 toxin, a mycotoxin produced by the genus Fusarium, is widely prevalent in agricultural products and livestock feed, posing substantial health risks to livestock and humans. This toxin induces oxidative stress in testicular Sertoli cells, disrupts testicular architecture, and compromises spermatogenesis. Despite its widespread presence in contaminated feeds, effective therapeutic strategies to counteract T-2 toxin-induced reproductive toxicity in Sertoli cells remain elusive. This study evaluated the protective efficacy and molecular mechanisms of proanthocyanidins (PCs), a phytochemical with antioxidant properties, against T-2 toxin-induced damage in yak (Bos grunniens) Sertoli cells. The findings revealed that T-2 toxin markedly reduced the viability of yak Sertoli cells and stimulated the production of reactive oxygen species (ROS). Treatment with 10 μg/mL PCs significantly enhanced cell viability, decreased apoptosis, and preserved cellular functions. Furthermore, PCs reduced ROS levels in yak Sertoli cells exposed to T-2 toxin and improved antioxidant capacity by upregulating the nuclear factor erythroid derived 2-like (NRF2)/heme oxygenase-1 (HO-1) signaling pathway. Additionally, PCs inhibited mitochondria-mediated apoptosis, diminished the occurrence of malformed mitochondria, and enhanced the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) signaling pathway associated with mitochondrial biogenesis in yak Sertoli cells exposed to T-2 toxin. This study provides novel insights into the prevention and treatment of T-2 toxin-induced reproductive damage in yaks and underscores the potential application of PCs in this context. Full article

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation, epithelial barrier disruption and immune dysfunction. Alleviating and curing these pathological manifestations is the goal of IBD treatment. Despite substantial advances in targeted immunotherapies and anti-inflammatory strategies, achieving sustained intestinal mucosal healing remains a major clinical challenge. Dynamin-related protein 1 (Drp1) is a GTPase that mediates mitochondrial fission and plays a crucial role in maintaining the dynamic balance of mitochondrial morphology and function. In IBD, Drp1 expression is frequently upregulated and continuously activated, resulting in excessive fission and fragmentation of mitochondria. This mitochondrial dysregulation contributes to ATP depletion and excessive reactive oxygen species (ROS) production, thereby exacerbating disease progression and amplifying inflammatory signaling. This review highlights the distinctive role of Drp1 as an integrative node in IBD. Specifically, we connect mitochondrial dynamics with epithelial barrier failure, immune dysregulation, inflammatory cell death, and intestinal microenvironment remodeling. We further emphasize the potential relevance of Drp1 for biomarker-based patient stratification and mechanism-informed therapeutic targeting, thereby distinguishing this review from more descriptive accounts of mitochondrial dysfunction in intestinal inflammation. Full article

Today, microfluidics has become a revolutionary field of engineering due to its wide range of applications, including lab-on-a-chip devices, microscale biochemical reactors, drug delivery systems, and disease diagnostics. Efficient fluid mixing has been a significant challenge in these systems due to the dominance of laminar flow and low-Reynolds number conditions, where mixing relies primarily on slow molecular diffusion. It is very difficult to achieve rapid mixing and homogeneous mixing within a limited length. In this study, a bioinspired passive micromixer is developed based on the cristae architecture of mitochondria, which is known for maximizing surface area and transport efficiency in biological systems. The micromixer incorporates cristae-like microstructures within a straight microchannel to produce continuous flow deflection, stretching, and folding, thereby promoting chaotic advection without relying on external energy sources. It also includes mitochondrial granules, such as micropillars, within the channel to disrupt streamline flow. Thus, a numerical investigation was conducted to design four different micromixer geometries: conventional T-channel, and T-channels with a single, double and triple matrix of cristae. The analysis was performed in COMSOL Multiphysics, in which “Laminar flow” and “Transport of diluted species” physics were used, and a stationary study was executed. Simulations were conducted at different Reynolds numbers (Re = 0.1–100) to observe the feasibility of the proposed designs. For analysis, the mixing index and concentration profiles at the outlet and along the length were also examined. The results showed that the high cristae density channel performed well, achieving a mixing index of 95.85% at Re = 0.1 and 85.84% at Re = 100, proving that the proposed mitochondria-inspired cristae Mito-mixer delivers efficient mixing over a broad Reynolds-number range while maintaining a compact, length-efficient design. Full article

Oxidative stress is one of the few defined causes of male infertility affecting at least one third of patients attending infertility clinics. Human spermatozoa are vulnerable to this form of attack because their stripped-down architecture means that they possess limited antioxidant protection and little capacity for biochemical repair. They also compound their vulnerability by being active generators of reactive oxygen species (ROS) and possessing multiple substrates for oxidative damage. The major sources of ROS in these cells are their mitochondria, an L-amino acid oxidase (IL4I1) and a calcium-dependent NADPH oxidase (NOX5). Spermatozoa tolerate the risks associated with ROS generation because their biology is heavily dependent on redox regulation. ROS are important mediators of sperm capacitation, stimulating the generation of cAMP and prostaglandins, inhibiting protein phosphatases and encouraging removal of cholesterol from the plasma membrane. Furthermore, during fertilization, the ability of ROS to activate metalloproteinases facilitates penetration of the zona pellucida and sperm–oocyte fusion. While ROS are physiologically important for sperm function, the over-production of these metabolites can impair sperm function. Antioxidants have therefore assumed some importance as a possible therapy for the infertile male. However, before this potential can be realized, we need to optimize the composition and dose of reagents used in such formulations and develop improved methods of diagnosing oxidative stress within the patient population. Full article

Chemotherapy-induced mucositis (CIM) is a dose-limiting toxicity of cancer therapy that is mainly associated with mitochondrial dysfunction in epithelial cells. We investigated whether GV1001, a mitochondrial protective peptide from human telomerase reverse transcriptase (hTERT), attenuates 5-fluorouracil (5-FU)-induced mucositis in a murine model. 5-FU induced notable mortality, leukopenia, and mucositis in the gastrointestinal (GI) tract, including tongue, esophagus and small intestine. It promoted epithelial–mesenchymal transition (EMT), nuclear factor kappa-B (NF-κB) activation, systemic and mucosal inflammation, DNA damage, impaired cell proliferation, and apoptosis throughout the GI tract. GV1001 blocked 5-FU–associated mortality, significantly attenuated leukopenia, and notably prevented mucositis. GV1001 also suppressed 5-FU-induced DNA damage, EMT, loss of proliferative capacity, apoptosis, and NF-κB activation in mucosal epithelium. In normal human keratinocytes, 5-FU inhibited the cell proliferation, disrupted mitochondrial function, as evidenced by reduced mitochondrial membrane potential, increased reactive oxygen species (ROS) production, impaired electron transport chain (ETC) complex integrity, decreased ATP synthesis, and cytochrome c release into the cytosol. GV1001 markedly mitigated these 5-FU-induced mitochondrial defects. Taken together, GV1001 mitigates CIM by most likely preserving mitochondrial integrity and function, supporting its potential as a strategy to prevent cancer chemotherapy-associated mucosal injury in patients. Full article

Mitochondrial dysfunctions contribute to the pathogenesis of tauopathies, a group of neurodegenerative diseases with abnormal accumulation of microtubule-associated protein tau. The combination of 5-aminolevulinic acid (5-ALA) and sodium ferrous citrate (SFC) is known to improve mitochondrial functions. Here, we report that 5-ALA combined with SFC (5-ALA/SFC) improves mitochondrial functions and mitigates neurodegeneration in transgenic Drosophila expressing human tau. We found that tau reduces ATP levels, decreases mitochondrial distribution to neurites, and increases mitochondrial reactive oxygen species (ROS). Expression of oxidative phosphorylation (OXPHOS) genes was upregulated, and activities of complexes I and IV were elevated. Feeding 5-ALA/SFC to tau flies lowers oxidative damage without correcting OXPHOS activities or mitochondrial distribution. 5-ALA/SFC treatment suppressed pathological tau phosphorylation and mitigated tau-induced neurodegeneration. These results suggest that 5-ALA/SFC attenuates a neurodegenerative pathway involving tau, mitochondria, and ROS. Full article

The redox mechanisms of RAW 264.7 macrophages exposed to 2.45 GHz RF-EMF at subthermal specific absorption rates and to lipopolysaccharide (LPS) and/or the SARS-CoV-2 spike protein (CSP) were investigated. To this end, cellular responses (lysosomal and mitochondrial activity, nitric oxide (NO) production, and cell survival/death) were measured after 6, 24, and 48 h. Selective loss of viability in cells exposed to RF and LPS was observed at 6 h, consistent with early defects in membrane permeability. Lysosomal activity was significantly enhanced in cells treated with RF + LPS. Mitochondrial activity decreased in cells exposed to RF + LPS at 6 h and increased in cells treated with RF + CPS/LPS. Cell viability decreased greatly in cells treated with LPS and CSP + LPS after 24, particularly after 48 h. Nitrite levels peaked in non-irradiated cells treated with RF + LPS and in CSP + LPS at 24 h and decreased in irradiated cells after 48 h. Irradiation affected selection of the death mode: apoptosis decreased or remained unchanged in cells subjected to any of the treatments, while necrosis increased in cells treated with CPS, LPS, or both for 48 h. The combination of RF-EMF and infectious agents reprogrammed the interaction between mitochondria/lysosomes/nitric oxide (NO)/cell death in macrophages in a time- and stimulus-dependent manner. Full article

Ototoxicity is traditionally viewed as a local cochlear adverse effect of indispensable therapies such as cisplatin and aminoglycosides. However, emerging evidence suggests that cochlear vulnerability is shaped by systemic physiology, including inflammatory tone, vascular barrier integrity, and metabolic state. In this Review, we propose a Gut–Mito–Ear axis in which gut ecosystem function influences circulating mediator modules that converge on two cochlear mediator nodes: blood–labyrinth barrier (BLB) gating and mitochondrial stress tolerance. We synthesize evidence showing that gut perturbation can alter cochlear outcomes in vivo, that at least one microbiota-derived metabolite signal can directly protect hearing in experimental settings, and that BLB dysfunction and inflammatory trafficking are mechanistically relevant to cisplatin- and aminoglycoside-induced injury. We further organize the literature using an evidence-weighted framework that distinguishes direct cochlear causality from mechanistic plausibility and explicitly retains negative studies as boundary-setting evidence. Finally, we outline a translational roadmap in which microbiome-targeted prevention is pursued through mediator-anchored, non-interference-aware strategies and evaluated across linked state variables spanning exposure context, gut function, defined mediator modules, BLB gating, mitochondrial stress tolerance, and auditory phenotype. The Gut–Mito–Ear axis is not considered an established mechanism. We present it as a falsifiable systems-biology model that organizes the current evidence. Within this model, we define the minimum and ideal standards for A-tier causal evidence, explicit criteria for interpreting boundary-setting negative (A−) studies, and a set of testable predictions for causal validation. Full article

Cardiac surgery represents a cornerstone of modern cardiovascular medicine, yet it is intrinsically linked to significant systemic stress responses that can compromise remote organ function. Among postoperative complications, cardiac surgery-associated acute kidney injury (CSA-AKI) remains a significant clinical challenge characterized by high morbidity and complex pathophysiology. While hemodynamic instability and ischemia–reperfusion injury are established risk factors, renal dysfunction frequently persists despite optimal perfusion. This observation suggests the involvement of potent circulating mediators in cellular injury. Extracellular vesicles (EVs) are essential for intercellular communication and serve as central hubs for transporting bioactive lipids, proteins, and genetic material. Accumulating evidence indicates that the mechanical and oxidative stress inherent to cardiopulmonary bypass triggers substantial release of EVs from platelets, erythrocytes, and injured vascular tissues. These vesicles may function as vectors that traffic oxidized mitochondrial components and pro-inflammatory cargo to the renal parenchyma. This signaling cascade appears to disrupt renal homeostasis through a proposed “dual-hit” mechanism involving the induction of endothelial dysfunction and endothelial-to-mesenchymal transition (EndMT), followed by tubular epithelial injury via mitochondrial fragmentation, redox imbalance, and downregulation of anti-aging factors. The complexity of these EV-mediated interactions may contribute to an incomplete understanding of why specific patient phenotypes fail to recover. This narrative review examines the mechanisms of surgery-induced EV biogenesis, the molecular pathogenesis of endothelial and tubular damage, and the role of intercellular crosstalk. Additionally, we discuss future perspectives on targeting the “EV vector” through therapeutic apheresis and mitochondrial pharmacotherapy to potentially improve clinical outcomes in high-risk surgical patients. Full article

Triple-negative breast cancer (TNBC) remains one of the most challenging subtypes of breast cancer to treat, defined by its molecular heterogeneity, absence of hormone receptors, and poor clinical outcomes. While this difficulty with cancer cells persists even in the presence of chemotherapy and immune checkpoint inhibitors (ICIs), one critical factor linked to both chemoresistance and immune escape is autophagy. Autophagy is a cellular process with lysosomal recycling function. In TNBC, autophagy paradoxically shifts from tumor-suppressive to a tumor-promoting role. Autophagy was initially known to maintain genomic stability and alleviate oxidative damage. In TNBC, cancer cells use autophagy to detoxify platinum-induced DNA. damage, clear damaged mitochondria via mitophagy, recycle critical macromolecules, and sustain dormancy in cancer stem-like cells (CSCs). At the same time, the process of autophagic flux facilitates immune evasion, including PD-L1 expression stabilization, MHC-I degradation, and the establishment of an immunosuppressive tumor microenvironment (TME). The review encapsulates the progressive concepts of molecular regulation of autophagy, which involve key factors such as ULK1, VPS34, and non-coding RNAs (ncRNAs). These factors play a significant role in chemoresistance, taxanes, anthracyclines, and platinum compounds. The review also discusses various strategies for translation that aim to circumvent or suppress autophagy-mediated chemoresistance, including autophagy inhibitors, natural compounds, and nanoparticle-based formulations, with a focus on their synergistic potential with ICIs and chemotherapeutic agents. Targeting autophagy has shown considerable potential for effectively addressing chemoresistance in TNBC. Future studies should focus on addressing chemoresistance and immunoresistance through autophagy-based therapies. Full article

Cytochrome c (Cytc) tyrosine 48 (Y48) has been previously shown to be phosphorylated in bovine liver, and phosphomimetic substitution (Y48E) inhibits key functions of Cytc in vitro, including respiration and apoptosis. In this study, we investigated the effect of Y48 modification in a double-knockout cell culture model that stably expressed either unphosphorylated wild-type (WT) Cytc, control Y48F Cytc, or phosphomimetic Y48E Cytc. Our findings revealed that Y48E Cytc caused partial inhibition of mitochondrial respiration in intact cells, which corresponded with lower mitochondrial membrane potentials (ΔΨ_m) and reduced reactive oxygen species (ROS) production. When subjected to an oxygen–glucose deprivation/reoxygenation (OGD/R) model, which simulates ischemia/reperfusion injury, the Y48E phosphomimetic cell line showed lower ROS production compared to the unphosphorylated WT and Y48F Cytc cell lines, the latter of which generated higher levels of ROS upon reoxygenation. As a result, the Y48E Cytc cell line had significantly lower cell death rates when exposed to OGD/R, confirming the cytoprotective role of Y48 phosphorylation of Cytc. In summary, our research indicates that the loss of Y48 phosphorylation in Cytc during ischemia leads to reperfusion injury by driving maximum electron transport chain flow, hyperpolarization of ΔΨ_m, bursts of ROS, and death of cells through apoptosis. Full article

The most common complication of active brucellosis in humans is osteoarticular injury. In the bone marrow microenvironment, mesenchymal stem cells (MSCs) can differentiate into either adipocytes or osteoblasts, and this balance is tightly regulated because an increase in adipogenesis may negatively affect bone formation and favor bone loss. The differentiation of MSCs into adipocytes or osteoblasts is tightly regulated by mechanisms that promote cell fate toward one lineage while repressing the other. Our study demonstrated that Brucella abortus infects MSCs but does not affect the deposition of organic and mineral matrix during osteoblast differentiation. However, the infection upregulates Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) expression in osteoblasts, which may contribute to osteoclast activation and bone resorption. Conversely, B. abortus infection significantly influences adipocyte differentiation by modulating lipolysis, lipogenesis, and interactions between lipid droplets and mitochondria. This leads to increased cellular cholesterol levels and reduced intracellular triglycerides, accompanied by glycerol release. These changes result in more differentiated adipocytes and larger lipid droplets. Consequently, we observed increased IL-6 secretion and a higher leptin/adiponectin ratio. Importantly, these effects were independent of a functional type IV secretion system (T4SS), as purified Brucella DNA fully reproduced the adipogenic phenotype. Moreover, inhibition of TLR9—the primary sensor of bacterial DNA—significantly reduced the DNA-induced adipogenic response, demonstrating that adipocyte modulation is at least in part mediated through TLR9 signaling. In summary, B. abortus promotes MSC differentiation toward an inflammatory adipocyte phenotype. It involves a TLR-9-mediated DNA detection. It may contribute to osteoarticular injury and infection-associated bone resorption. Full article