Search Results (402)

Carfilzomib (CFZ) is a proteasome inhibitor primarily used to treat relapsed and refractory multiple myeloma. However, its clinical application is limited by significant cardiotoxicity, the underlying mechanisms of which remain incompletely understood. In this study, we aimed to elucidate the pathogenic pathways involved. In vitro, CFZ induced mitochondrial dysfunction and apoptosis in AC16 cardiomyocytes in a concentration- and time-dependent manner. Transcriptomic analysis revealed enrichment in pathways related to autophagy and endoplasmic reticulum stress. Mechanistically, CFZ promoted autophagosome formation but downregulated the SNARE proteins STX17, SNAP29, and VAMP8, thereby impairing autophagosome–lysosome fusion and blocking autophagic flux. This disruption was associated with the activation of the cGAS-STING signaling pathway. In vivo, CFZ administration resulted in cardiac dysfunction and apoptosis in mice, both of which were attenuated by the STING inhibitor C-176. Consistently, STING knockdown restored autophagic flux and reduced cardiomyocyte injury in vitro. In conclusion, CFZ induces cardiotoxicity by activating the cGAS-STING pathway, which disrupts the autophagic clearance of damaged mitochondria and promotes cardiomyocyte apoptosis. Targeting STING may represent a promising therapeutic strategy to mitigate CFZ-induced cardiotoxicity. Full article

Mitochondrial dysfunction is not merely a byproduct of transformation but a driver of tumorigenesis, metastasis, and therapeutic resistance. Recent advancements in intercellular communication have identified Extracellular Vesicles (EVs) or exosomes as critical mediators that bridge the gap between the tumor and its microenvironment (TME). These EVs contain a complex repertoire of bioactive cargo, including proteins, lipids, and RNAs. Among the class of RNAs, small non-coding RNAs, microRNAs (miRNAs), are the most abundantly expressed bioactive compounds that are selectively packaged and delivered to recipient cells. EV-delivered miRNAs can target nuclear-encoded mitochondrial genes and have also been reported to localize to mitochondria (mitomiRs), where they function as post-transcriptional regulators of bioenergetic and mitochondrial dynamic adaptations that support tumor progression. This review explores the “EV-miRNA-Mitochondria Axis”, delineating the molecular mechanisms by which EV-carried miRNAs reprogram the “Mitochondrial Information Processing System” (MIPS) - a signaling network where mitochondria integrate metabolic cues (e.g., ROS, calcium flux) to dictate critical biological outcomes, such as immune regulation and cell survival. We summarized specific sorting machineries (e.g., hnRNPA2B1, Lupus La) that package oncogenic miRNAs into EVs and how these cargoes hijack mitochondrial function upon delivery. Specifically, we discussed how EV-miRNAs induce metabolic shifts, manipulate mitochondrial dynamics (fission/fusion), and inhibit the intrinsic apoptosis to drive cancer progression. Finally, we highlighted the dual utility of these EV-miRNAs as drivers of pathogenesis and promising non-invasive biomarkers for early diagnosis, prognostic and therapeutic monitoring. Full article

Mitochondria play essential roles in cellular metabolism and signaling, regulating biosynthetic pathways, calcium homeostasis, redox balance, and cell fate beyond ATP production. Their continual remodeling through fusion, fission, and mitophagy maintains mitochondrial quality control and adapts organelle function to cellular demands. Here, we review how mitochondrial dynamics, fusion, fission, and mitophagy modulate metabolic reprogramming and signaling to drive cancer progression and therapy resistance. Emerging evidence indicates that in cancer, mitochondrial fusion enhances respiratory efficiency and oxidative phosphorylation, whereas fission promotes glycolytic adaptation, rapid biomass accumulation, and stress tolerance. Mitophagy further refines metabolic fitness by eliminating damaged mitochondria and sustaining redox homeostasis. Together, these processes underscore that dysregulation of mitochondrial dynamics is a hallmark of cancer and a key driver of metabolic reprogramming and therapeutic resistance. In this review, we summarize how mitochondrial fusion, fission, and mitophagy govern metabolic circuitry in cancer development and therapy resistance. We highlight their functional impact on tumor progression and discuss emerging therapeutic strategies targeting mitochondrial dynamics and associated machinery. Understanding this dynamic metabolic crosstalk may reveal new vulnerabilities and guide the development of mitochondria-targeted cancer therapies. Full article

Colorectal cancer (CRC) progression stems from dynamic metabolic crosstalk between malignant cells and the tumor microenvironment (TME). Among stromal components, cancer-associated fibroblasts (CAFs) have emerged as pivotal metabolic drivers rather than mere structural elements. Specifically, evidence indicates that mitochondrial reprogramming in CAFs significantly orchestrates tumor growth, therapeutic resistance, and immune evasion in CRC. This review synthesizes recent insights into how CAF mitochondrial dynamics and metabolic reprogramming dictate CRC biology. We first examine the functional diversity of CAF subpopulations and their distinct mitochondrial requirements. We then contrast mitochondrial dynamics—including fission–fusion balance and mitophagy—between CRC cells and CAFs, highlighting how tumor-derived signals modulate stromal mitochondrial function. We systematically evaluate key regulatory pathways of CAF mitochondrial reprogramming, including TGF-β/HIF-1α, ROS-NF-κB, PI3K–AKT–mTOR, AMPK–PGC-1α, YAP/TAZ mechanotransduction, and mtDNA-mediated cGAS–STING signaling. Furthermore, we discuss how remodeled CAF mitochondria foster metabolic symbiosis via lactate, ketone, and glutamine shuttling; maintain redox homeostasis through the NADPH–glutathione axis and UCP2; and establish immunosuppressive niches via mitochondrial stress signaling. Collectively, these mechanisms drive resistance to chemotherapy, targeted agents, radiotherapy, and immunotherapy. By integrating mitochondrial metabolism, stromal signaling, and clinical responses, this review identifies CAF mitochondria as an actionable target within the CRC TME. Targeting these CAF-specific pathways offers a novel strategy to disrupt tumor–stroma metabolic cooperation and overcome treatment resistance in colorectal cancer. Full article

Intercellular mitochondrial trafficking has emerged as an important mechanism influencing tumor progression, metabolic adaptability, and cancer cell plasticity. Beyond their classical bioenergetic functions, mitochondria act as central regulators of redox homeostasis, signaling pathways, and epigenetic remodeling. Increasing evidence suggests that mitochondria can be transferred between tumor, stromal, and immune cells through tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junctions, and cell fusion within the tumor microenvironment. This dynamic excshange enables metabolically compromised cancer cells to restore oxidative phosphorylation, optimize energy production, and survive under hypoxia and therapeutic stress. Mitochondrial transfer has been increasingly associated with enhanced cellular plasticity and adaptive phenotypic transitions, including the acquisition of stem-like features that contribute to tumor heterogeneity, metastasis, and treatment resistance. In addition to bioenergetic restoration, transferred mitochondrial DNA and metabolites participate in retrograde signaling, linking metabolic state to epigenetic regulation and transcriptional reprogramming. This metabolic epigenetic interplay supports tumor cell adaptation to environmental stress and therapeutic pressure. Although significant progress has been made, the precise mechanisms governing mitochondrial integration and their long-term impact on cellular phenotypes remain incompletely understood. A deeper understanding of these processes may reveal novel therapeutic strategies to disrupt tumor adaptability and progression. Specifically, targeting intercellular mitochondrial trafficking and its associated metabolic and epigenetic effects could help limit tumor plasticity, overcome treatment resistance, reduce disease recurrence, and improve overall clinical outcomes in cancer patients. Full article

The family of Nek kinases has 11 human members that are conserved in their kinase domains but diverse in their regulatory domains. Functionally, they can be associated with diverse aspects of cell cycle regulation, from mitosis and primary cilia function to centrosome disjunction in the G2 phase and checkpoints of the DNA damage response. However, novel functional contexts have emerged in recent years, including regulatory roles of Neks 1, 4, 5, and 10 in mitochondrial metabolic and morphological homeostasis. We recently generated, by CRISPR-Cas9 technology, a DU-145 prostate cancer cell line, with an NEK6 gene knockout. Here, we focus on a detailed characterization of changes in this cell line, in mitochondrial respiration function and morphology. DU-145 NEK6 knockout cells exhibited reduced mitochondrial respiration and a fragmented phenotype in electron microscopy, with reduced mitochondrial cristae numbers. Alterations in mitochondrial architecture and respiration were correlated with increased expression of anaerobic glycolytic proteins (HK2, PFKP, and LDHA) and decreased expression of PDH, an enzyme of aerobic glycolysis. Molecular analysis by Western blot revealed decreased levels of mitochondrial mass and biogenesis protein markers (TOM20, TFAM), without alterations in other markers such as VDAC1/3 or mtDNA copy number in the NEK6 knockout cells. Furthermore, the regulators of mitochondrial fusion/fission are altered in the knockout cells (decrease in the Long-OPA1:Short-OPA1 ratio and DRP1 total level), which is associated with an increase in endoplasmic reticulum–mitochondria contact at ≤20 nm observed in transmission electron microscopy (TEM) image analysis. Using analysis of TEM micrographs, we found an increase in the autophagic structures (autophagosome, amphisome, and autolysosome), with mitochondria as cargo in some structures, which was correlated with a decrease in LC3A/B and an increase in the BECLIN1 total level, and with an increase in acidic vesicles approximation, suggesting that reduction in TOM20 and TFAM without alterations in VDAC1/3 and mtDNA copy number might be related to mitochondrial degradation through autophagy. Together, our data suggest a new role for NEK6 in regulating mitochondrial homeostasis, where its loss alters mitochondrial morphology and respiration, and could be associated with an increase in the degradation of the dysfunctional mitochondria through autophagy. Full article

Pneumoconiosis, characterized by progressive pulmonary fibrosis, remains a predominant occupational disease in China, with coal workers’ pneumoconiosis (CWP) and silicosis being the primary subtypes. Despite extensive research, its underlying pathogenic mechanisms are not yet fully understood. Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are crucial subcellular microdomains that govern Ca²⁺ transport, sustain cellular bioenergetics, and maintain systemic homeostasis. Emerging evidence has linked the structural and functional dysregulation of MAMs to the pathogenesis of various fibrotic disorders. Apoptosis, a highly regulated cell death process, is a key driver in pneumoconiosis progression, in which Ca²⁺ imbalance serves as a critical signaling cascade. Mitofusin 2 (MFN2), a core regulator of MAMs’ structural integrity, mediates mitochondrial fusion and directly bridges the ER with the outer mitochondrial membrane, thereby stabilizing ER–mitochondrial coupling. However, whether MFN2 mitigates fibrosis by preserving MAMs’ integrity and subsequently suppressing Ca²⁺-dependent apoptosis remains elusive. In this study, we established SD rat and A549 cell models of CWP. Our results demonstrated that MFN2 expression was downregulated after coal dust exposure, accompanied by MAMs impairment, Ca²⁺ imbalance, and increased apoptosis, which ultimately drove the pathological progression of pulmonary fibrosis. Notably, MFN2 overexpression restored MAMs’ structure and Ca²⁺ homeostasis, alleviated abnormal apoptosis, and subsequently inhibited fibrosis. This study highlights the importance of the MFN2–MAMs–Ca²⁺–apoptosis axis and identifies MFN2 as a potential therapeutic target for pneumoconiosis. Full article

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

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

Background/Objectives: Mitochondria are dynamic organelles that continuously undergo balanced cycles of fusion and division to maintain optimal function. Mitochondrial division is mediated by Dynamin-Related Protein 1 (DRP1), a cytosolic large GTPase whose phosphorylation at serine 616 (DRP1-S616Ⓟ) promotes its translocation to the outer mitochondrial membrane and organelle division. Dysregulated mitochondrial division disrupts cellular homeostasis and contributes to disease pathogenesis, including cancer. Our prior work demonstrated that the oncogene-induced mitogen-activated protein kinase (MAPK) pathway constitutively phosphorylates DRP1 at serine 616, which is essential to cellular transformation and correlates with oncogene status in patient tissues. Similarly, DRP1-S616Ⓟ is subject to pharmacologic control by targeted therapies against oncogenic MAPK signaling. Methods: Building upon this foundation, we developed and characterized a recombinant murine monoclonal antibody (referred to as 3G11) with high specificity for human DRP1-S616Ⓟ, raised against a peptide derived from the human DRP1 sequence. Results: Using diverse experimental platforms, we demonstrate the robust utility of 3G11 to detect DRP1-S616Ⓟ in melanoma cell extracts and isolated organelles. Immunofluorescence revealed that pharmacologic inhibition of oncogenic MAPK signaling reduces DRP1-S616Ⓟ levels, which correlates with mitochondrial hyperfusion, while immunohistochemistry showed that elevated DRP1-S616Ⓟ expression in human tissues correlates with BRAF^V600E disease. Conclusions: 3G11 is a new recombinant antibody for detecting DRP1-S616Ⓟ and supports studies of mitochondrial division in cancer. Together, these findings establish 3G11 as a specific, versatile, renewable, and cost-effective tool for studying mitochondrial division, with strong potential for clinical applications. Full article

Beyond their classical role as “cellular powerhouses”, mitochondria are increasingly recognized as dynamic and interconnected networks whose architecture, quality control, and intercellular communication influence cellular and organismal homeostasis. Mitochondrial dynamics—including fusion–fission balance, mitophagy–biogenesis coupling, intracellular organization, and intercellular transfer via tunneling nanotubes, extracellular vesicles, or transient cell fusion—contribute to tissue adaptation and functional decline during aging. Focusing on cardiac muscle, skeletal muscle, and the nervous system, this narrative review synthesizes current evidence describing how aging disrupts mitochondrial network integrity through altered dynamics, impaired organelle positioning and transport, reduced mitophagy, mtDNA instability, and compromised metabolic coupling between cells. These alterations propagate across tissues, limiting energetic flexibility, stress resilience, and regenerative capacity. Building on these mechanisms, we discuss a systems-level perspective in which aging is associated with progressive loss of mitochondrial network coherence rather than solely cumulative molecular damage. Within this framework, mitochondrial connectivity functions as an integrative descriptor of cellular resilience: well-organized networks counteract metabolic perturbations, whereas functionally decoupled networks amplify stress and promote maladaptive aging trajectories. Emerging evidence indicates that physiological and pharmacological interventions, including endurance exercise, caloric restriction or mimetics, fusion-supporting pathways, and mitophagy-enhancing strategies, can partially restore network organization even later in life. Molecular, cellular, and tissue-level insights are integrated to highlight mitochondrial network dynamics as both a mechanistic contributor to aging and a potentially modifiable target for future preventive and therapeutic interventions. Full article

Cannabidiol is a non-psychoactive compound originating from Cannabis sativa L., with a promising therapeutic profile that influences numerous cellular processes. A major area of interest is its impact on mitochondria, organelles essential for cellular metabolism, ATP production, calcium homeostasis, and stress response. This article explores the available data on contribution of CBD effect on mitochondria to its therapeutic potential in treatment of various pathologies: cancer, cardiovascular, lung, neurological, gastrointestinal and liver disease, and muscle pathologies. Regarding cancer, the cytotoxic effects of cannabidiol on glioma, leukaemia, non-Hodgkin lymphoma, prostate, gastric, and breast cancer are analysed. In the case of cardiomyopathies and heart failure, cannabidiol plays an important role in reducing oxidative stress and promoting mitochondrial biogenesis. In lung diseases, cannabidiol reduces the expression of mitochondrial fission genes and increases the expression of fusion genes. When it comes to neurological pathologies, cannabidiol protects neurons and exhibits a strong antioxidant effect, while in gastrointestinal and liver diseases, cannabidiol stabilises mitochondrial membrane potential, increases ATP production, and reduces oxidative stress. In muscle affections, cannabidiol improves mitochondrial function by inhibiting excessive mitophagy. Although modern formulations may improve the low bioavailability of CBD, its potential non-selective cytotoxicity toward non-malignant cells remains an important concern that warrants further investigation. Nevertheless, cannabidiol possesses a remarkable therapeutic potential, and its effects on mitochondria open new perspectives in the treatment of numerous diseases. Full article

Background: Mitochondria are multifunctional organelles that play a central role in maintaining cellular homeostasis by regulating energy metabolism, reactive oxygen species (ROS) generation, ion homeostasis, and apoptotic signaling. Dynamic processes such as mitochondrial fission, fusion, and intracellular trafficking enable cells to adapt to metabolic and environmental stress. Growing evidence indicates that dysregulation of these processes is a hallmark of cancer, contributing to metabolic reprogramming, redox imbalance, evasion of apoptosis, and disease progression. This narrative review aims to discuss the role of mitochondrial alterations in the pathophysiology of chronic myeloid leukemia (CML) and their potential therapeutic implications. Methods: Original research articles published between 2010 and 2025 were considered in this narrative review. The selected studies were critically discussed and categorized into three principal thematic domains: mitochondrial regulation of redox homeostasis, metabolic rewiring, and control of cell death pathways. Evidence was synthesized to elucidate the contribution of mitochondrial dysfunction to CML initiation, progression, and therapeutic resistance. Results: The reviewed studies highlight how mitochondrial abnormalities play a pivotal role in BCR-ABL1-driven leukemogenesis. Alterations in mitochondrial metabolism and ROS signaling support sustained proliferative signaling, promote genomic instability, and facilitate resistance to apoptosis. In addition, mitochondrial adaptations contribute to resistance to tyrosine kinase inhibitors (TKIs) and are essential for the persistence and survival of leukemic stem cells. Conclusions: Mitochondria emerge as central regulators of CML pathobiology. Therapeutic strategies targeting mitochondrial metabolism, redox homeostasis, and apoptotic signaling pathways represent promising approaches to overcoming TKI resistance and may improve clinical outcomes for patients with CML. Full article

PCSK9 is a gene associated with familial hypercholesterolemia and is involved in other biological processes such as apoptosis, autophagy, and inflammatory responses. This study aims to further validate whether PCSK9 inhibitors can improve diabetic cardiomyopathy and elucidate their mechanisms of action. This study utilized H9c2 cells and C57BL/6J mice to validate the efficacy of the PCSK9 inhibitor alirocumab through in vivo and in vitro experiments. In vitro, alirocumab was shown to enhance cell viability and reduce oxidative stress in H9c2 cells under high glucose stress. It can also decrease the expression levels of inflammatory reaction and mitochondrial apoptosis-related proteins. Through in vivo experiments, we demonstrated that alirocumab can reduce myocardial hypertrophy and improve cardiac function in diabetic cardiomyopathy mice. Meanwhile, alirocumab treatment increased mitochondrial size and quantity in the hearts of diabetic cardiomyopathy mice, promoted mitochondrial fusion, and reduced the number of damaged mitochondria. Alirocumab could also reduce the percentage of myocardial fibrosis and oxidative stress in mice. Finally, we found that alirocumab can improve cardiac function in diabetic cardiomyopathy through the ERK/p38 MAPK pathway. Our data demonstrate that the PCSK9 inhibitor alirocumab provides protective effects against diabetic cardiomyopathy, offering fundamental experimental support for its clinical application in this condition. Full article

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder, yet its pathogenic mechanisms remain incompletely understood, highlighting the need for reliable experimental models. We previously developed a murine model based on inhalation of a manganese mixture (MnCl₂ and Mn(OAc)₃), which reproduces dopaminergic neuron loss in the substantia nigra pars compacta (SNc) and motor impairment. However, its capacity to mimic mitochondrial dysfunction, a key mechanism in PD, had not been explored. This study evaluated mitochondrial ultrastructure, fission and fusion proteins, and the activity of electron transport chain complexes I and IV, alongside fine motor performance. Forty male CD1 mice were divided into control (deionized water) and manganese-exposed groups (0.04 M MnCl₂ + 0.02 M Mn(OAc)₃), inhaled for 1 h twice weekly over five months. Manganese inhalation induced significant fine motor deficits, increased mitochondrial number with reduced area and circularity, and disorganized cristae. Drp1 and Fis1 levels were elevated, accompanied by decreased activity of complexes I and IV, predominantly in the SNc. These findings demonstrate that this progressive, bilateral model reproduces mitochondrial and motor alterations resembling those observed in PD, supporting its utility for testing mitochondria-targeted therapeutic strategies. Full article