Search Results (399)

(1) Background: Mild traumatic brain injury (mTBI), the most prevalent form of traumatic brain injury, often results from repetitive impacts to the head and is associated with long-term neurological impairment. The pathophysiology of mTBI is multifactorial and involves alterations in mitochondrial bioenergetics, a key determinant of neuronal function and survival. Although mitochondrial dysfunction is recognized as a hallmark of mTBI, its long-term effects on bioenergetics and the roles of regulatory cytosolic and mitochondrial proteins remain poorly understood. We hypothesized that repeated mTBI (rmTBI) induces sustained deficits in mitochondrial bioenergetics that are associated with long-term changes in key bioenergetic and other regulatory proteins. (2) Methods: Using the repeated CHIMERA injury model in adult male rats, randomly assigned to sham or rmTBI groups, we assessed mitochondrial respiration in isolated mitochondria and whole cerebral cortex homogenates using a Clark O₂ electrode and an Oroboros O₂k respirometer at time points ranging from 1 day to 2 months post-injury. Western blotting was performed for expression of regulatory proteins HKI, DRP1, MFN2, VDAC1, and ANT2. (3) Results: At 2 months post-rmTBI, respiration was faster and uncoupled, while ATP synthesis was significantly slowed compared with sham rats. This was accompanied by decreased expression of mitochondrial MFN2 and ANT2, by increased mitochondrial expression of DRP1, and by decreased translocation of HKI to mitochondria. There was no significant difference in VDAC1 expression. Earlier time points showed no significant differences in bioenergetics or protein expression, but neuro-inflammatory markers (GFAP and Iba1) were significantly elevated at these earlier time points of post-injury. (4) Conclusions: These findings indicate that rmTBI leads to a delayed long-term impairment of mitochondrial bioenergetics associated with alterations in proteins critical for bioenergetic regulation and mitochondrial control. This suggests a pathophysiologic mechanism for the persistent cognitive and behavioral deficits observed following rmTBI. 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

The etiology of autism spectrum disorder (ASD) implicates genetic predispositions and environmental chemicals, such as polybrominated diphenyl ethers (PBDEs). We aimed to identify whether mitochondrial quality control (MQC) was involved in ASD-relevant behavioral changes induced by decabromodiphenyl ether (deca-BDE, BDE-209) and the alleviation by melatonin. Pregnant rats exposed to BDE-209 (50 mg/kg i.g.) were administrated melatonin through drinking water (0.2 mg/mL) during gestation and lactation. Behavioral assessments integrated open-field test, three-chamber social test, and Morris water maze; mitochondrial detections took transmission electron microscopy, immunofluorescence, and homeostasis together; hippocampal molecular network was identified through transcriptomics profiles, combining dendritic morphology analysis after Golgi-Cox staining. Melatonin supplementation attenuated BDE-209-reduced social and cognitive ability, accompanied by improvements in hippocampal synaptic plasticity (dendritic spines, PSD95, SNAP25). Mitochondrial dysfunctions, shown as decreases in complex IV activity, ATP content, and mtDNA copies, plus redox imbalance (ROS/SOD2) and resultant mitochondrial membrane potential disruption and apoptosis, together with fusion/fission dynamic (MFN2/DRP1), biogenesis (SIRT1-PGC1α-TFAM), and mitophagy (SIRT3-FOXO3-PINK1) suppression, were reversed by melatonin partially through SIRT1 (Sirtuin-1)-dependent pathways, as these protections were abolished by inhibitor EX527. This study highlighted the SIRT1–SIRT3 axis in MQC and behavioral effects, providing novel intervention for PBDEs’ neurodevelopmental impairment. 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: Main risk factors associated with the development of sarcopenia (coexistence of muscle mass loss and dysfunction) are a sedentary lifestyle coupled with obesity. Associated mitochondrial dysfunction leads to energy deficits and perturbations in the balance between protein synthesis and degradation, thereby triggering muscle dysfunction or atrophy. Aside from exercise, which is challenging to implement and maintain, particularly in women, treatments for diminishing sarcopenia are scarce. The objective of the present study was to evaluate the effect of the flavanol (−)-epicatechin (EC) in a hypercaloric diet-induced obese female rat model. Muscle strength and endurance, as well as relative mitochondrial DNA content in skeletal muscle, were assessed. Methods: Female rats were fed a hypercaloric diet to induce obesity, as evidenced by increases in body weight, Lee index, and lipid profile alterations, and by abdominal fat accumulation, and to promote a sarcopenic phenotype. Functional tests of grip strength and mobility (treadmill) were performed. Mitochondrial relative content was evaluated by measuring the ratio of mtDNA/nuclear DNA, and the expression of genes related to mitochondrial biogenesis (Pgc1-α, Tfam), fusion (Mfn1 and Opa1), fission (Drp1 and Fis1), and mitophagy (Pink1 and Pkn), and function; citrate synthase and Ucp3 were also evaluated. Results: A significant decrease in mobility and strength was observed in obese female rats, accompanied by reduced mitochondrial numbers, activity, and dynamics, but not by changes in muscle size or weight. Treatment with EC induced mitochondrial biogenesis and positive changes in mitochondrial dynamics (fission and fusion) and activity, as measured indirectly by changes in citrate synthase and Ucp3 expression. Discussion: Results reinforce the potential of EC as a modulator of mitochondrial function in dysfunctional conditions associated with obesity, thereby attenuating the mechanisms underlying sarcopenia. Full article

7-ketocholesterol (7-KC) is a bioactive oxysterol generated under oxidative stress and may contribute to bone marrow niche reprogramming in acute myeloid leukemia (AML), thereby promoting stress tolerance and therapeutic resistance Bone marrow mesenchymal stromal cells (MSCs) from healthy donors and AML patients were exposed to subtoxic 7-KC concentrations for 24 h. We evaluated the ABC transporters involved in lipid transport, multidrug resistance and membrane microdomain remodeling; Hedgehog pathway proteins; stress–survival signaling; redox balance by glutathione measurements, and mitochondrial function and dynamics, including membrane potential and gene expression of mitochondrial fission and fusion regulators. Results were integrated using principal component analysis (PCA), heatmaps, and correlation-based networks. Multivariate analyses revealed an integrated, lineage-dependent response. Healthy donor MSCs showed greater plasticity of the efflux and microdomain axis and higher oxidative and mitochondrial vulnerability at high 7-KC doses. AML-MSCs exhibited a basal preconditioned state phenotype and preferentially routed the response toward Hedgehog and stress–survival modules, accompanied by glutathione expansion and adaptive mitochondrial remodeling. 7-KC acts as a broad modulator of several MSC functions, linking sterol homeostasis to Hedgehog signaling, stress–survival pathways, redox balance, and mitochondrial remodeling, potentially supporting a pro-survival, more therapy-tolerant leukemic niche. Full article

Novel therapeutic strategies are required to protect the heart from acute ischaemia-reperfusion injury (IRI) and improve outcomes in patients with acute myocardial infarction (AMI). Mitochondria play a critical role in determining cardiomyocyte fate following acute IRI, with genetic and pharmacological inhibition of Drp1-mediated mitochondrial fission limiting cardiomyocyte death. We investigated the role of the mitochondrial Drp1 receptors, MiD49 and MiD51, as novel targets for cardioprotection. In cardiac cell lines subjected to simulated IRI, dual genetic knockdown of both MiD49 and MiD51 reduced cell death, inhibited mitochondrial fission, prevented mitochondrial permeability transition pore opening, and attenuated mitochondrial calcium overload compared with wild-type cells. However, individual knockdown of either MiD49 or MiD51 did not induce mitochondrial elongation or inhibit MPTP opening. Whole-body genetic ablation of MiD49 in adult mice modestly altered mitochondrial morphology but did not affect myocardial infarct size or cardiac function following AMI. Together with the in vitro protection seen with dual MiD49/51 knockdown, these findings suggest that MiD49 deficiency alone is insufficient and that coordinated inhibition of MiD49 and MiD51 may be required for cardioprotection. 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

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

Mitochondria–endoplasmic reticulum contacts (MERCs) are physical structures formed between mitochondria and the endoplasmic reticulum (ER) through various tethering proteins, playing crucial roles in multiple physiological processes, including Ca²⁺ and lipid exchange between the ER and mitochondria, regulation of mitochondrial morphology and dynamics (fusion and fission), as well as the induction of autophagy and apoptosis. Mitofusin 2 (MFN2), a key mitochondrial fusion protein, has been identified as an essential structural component of MERCs. Our research demonstrates that 16:8 circadian intermittent fasting (CIF) leads to enhanced mitochondrial fusion. The upregulation of MFN2 reinforces MERC stability, thereby facilitating efficient Ca²⁺ transfer between the ER and mitochondria. This process sustains the activity of mitochondrial oxidative phosphorylation (OXPHOS) enzymes, elevates mitochondrial oxygen utilization efficiency, and ultimately augments ATP production. Consequently, these adaptations enhance cardiomyocyte tolerance to hypoxic conditions. This study elucidates a novel mechanism by which MERCs regulate cellular hypoxia resistance and proposes a potential therapeutic strategy for improving acute hypoxia tolerance through the modulation of Ca²⁺ transport at MERCs. Full article

Mitochondria are central regulators of cardiac homeostasis, integrating energy production, redox balance, calcium handling, and innate immune signaling. In cardiovascular disease (CVD), mitochondrial dysfunction acts as a unifying mechanism connecting oxidative stress, metabolic inflexibility, inflammation, and structural remodeling. Disturbances in mitochondrial quality control—encompassing fusion–fission dynamics, PINK1/Parkin- and receptor-mediated mitophagy, biogenesis, and proteostasis—compromise mitochondrial integrity and amplify cardiomyocyte injury. Excess reactive oxygen species, mitochondrial DNA release, and calcium overload further activate cGAS–STING, NLRP3 inflammasomes, and mPTP-driven cell death pathways, perpetuating maladaptive remodeling. Therapeutic strategies targeting mitochondrial dysfunction have rapidly expanded, ranging from mitochondria-targeted antioxidants (such as MitoQ and SS-31), nutraceuticals, metabolic modulators (SGLT2 inhibitors, metformin), and mitophagy or biogenesis activators to innovative approaches including mtDNA editing, nanocarrier-based delivery, and mitochondrial transplantation. These interventions aim to restore organelle structure, improve bioenergetics, and reestablish balanced quality control networks. This review integrates recent mechanistic insights with emerging translational evidence, outlining how mitochondria function as bioenergetic and inflammatory hubs in CVD. By synthesizing established and next-generation therapeutic strategies, it highlights the potential of precision mitochondrial medicine to reshape the future management of cardiovascular disease. Full article

Increasing evidence implicates mitochondrial/cellular dynamics in ischemia reperfusion (I/R)-induced acute kidney injury (AKI). Sodium-glucose-co-transporter-2 inhibitors (SGLT2is, e.g., canagliflozin, CG) have been shown to mitigate I/R-induced AKI. Here, we hypothesized that CG-improved AKI was associated with altered mitochondrial dynamics and apoptosis in a previously established swine model. CG (300 mg, PO) significantly increased pro-apoptotic genes Bid, Bad, Bax, Bak1 and Casp1 expression (all p < 0.05). Pink1 (p = 0.0019), Optn (p = 0.038), and Map1lc3 (p = 0.0093) expression also increased with CG, implicating mitophagy; PINK1 protein levels were unchanged. The expression of mitochondrial fission regulator Fis1 increased with CG treatment (p = 0.0015) while fusion regulator Opa1 expression decreased (p = 0.038). TUNEL staining showed increased apoptosis primarily in damaged proximal tubular cells of CG animals. Ki67 staining revealed I/R-injury increased cell proliferation throughout the kidney, which was significantly attenuated with CG. Moreover, correlative analysis revealed that AKI severity positively correlated with cell proliferation. In this large animal model, CG reduced AKI via increased mitochondrial fission and pro-apoptotic gene expression, potentiating clearance of damaged mitochondria, and decreased cell proliferation. Future studies should evaluate other SGLT2is as a potential therapeutic for I/R AKI. Full article

Alterations in mitochondrial fusion and fission dynamics are critical determinants of cellular fate. However, how stress-induced mitochondrial fusion and fission affect the physiological and pathological processes in cardiomyocytes remains poorly understood. Based on an established in vitro model of stress-induced cardiomyocyte injury using isoproterenol-treated H9c2 cells, this study aimed to investigate whether the dysregulation of mitochondrial dynamics—specifically, an imbalance between fusion and fission—activates the IRE1α-ASK1-JNK endoplasmic reticulum stress signaling pathway, thereby contributing to cardiomyocyte damage. Under this experimental paradigm, cell viability was evaluated using the CCK-8 assay. Concurrently, immunofluorescence staining was employed to assess reactive oxygen species accumulation, the expression of key mitochondrial fusion/fission proteins, and components of the ER stress pathway (IRE1α, ASK1, and JNK). Results demonstrated that isoproterenol treatment elevated intracellular ROS levels and induced significant changes in both mitochondrial dynamics-related proteins and the IRE1α-ASK1-JNK signaling axis. In contrast, administration of the mitochondrial fission inhibitor Mdivi-1 attenuated ROS accumulation, restored the expression of the affected proteins toward normal levels, and alleviated cardiomyocyte injury. Collectively, these findings indicate that the disruption of mitochondrial fusion/fission dynamics triggers endoplasmic reticulum stress via the IRE1α-ASK1-JNK cascade, which participates in the pathological progression of cardiomyocyte injury. Full article

Chemotherapy remains a cornerstone of systemic cancer treatment, yet dose-limiting toxicities—cardiotoxicity, neurotoxicity, and nephrotoxicity—affect 40–80% of patients, interrupt 20–30% of treatment cycles, and double long-term mortality. We propose that these seemingly distinct organ toxicities converge on a single mechanism: selective disruption of the MQC network. MQC comprises five interdependent modules—biogenesis, dynamics, mitophagy, proteostasis, and the recently characterized migrasome-mediated mitocytosis—collectively maintaining ATP supply, redox balance, and Ca²⁺ homeostasis in high-demand tissues. Chemotherapeutics such as anthracyclines, platinum agents, and taxanes simultaneously repress PGC-1α-driven biogenesis, hyperactivate Drp1-mediated fission, impair autophagosome–lysosome fusion, and inhibit mitocytosis, triggering mitochondrial collapse, ROS overflow, and cell death. This first-in-field review delineates organ-specific MQC pathways and catalogs druggable interventions—including small molecules, natural products, and nano-delivery systems—that restore MQC checkpoints. We present an integrated “MQC disruption–multi-organ toxicity–targeted intervention” framework, identifying Drp1 hyperactivation, late-stage mitophagy arrest, and mitocytosis inhibition as core therapeutic nodes. Targeting these pathways offers a promising strategy to decouple anticancer efficacy from off-target toxicity, potentially enabling optimized dosing, reducing treatment discontinuation, and improving long-term prognosis. Most MQC-targeted agents, however, remain in preclinical or early-phase trials. Full article

Mitochondria are highly dynamic organelles that integrate metabolic regulation, signal transduction, and programmed cell death with their canonical role in adenosine triphosphate (ATP) production. Their ability to undergo continuous remodeling through the opposing processes of fusion and fission is essential for maintaining cellular homeostasis, preserving organelle quality control, and enabling adaptive responses to metabolic and oxidative stress. Among the core regulators of mitochondrial dynamics, the dynamin-related guanosine triphosphatase (GTPase) OPA1 plays a central role in inner membrane fusion, cristae architecture maintenance, bioenergetic efficiency, and the modulation of redox balance and apoptotic signaling. Accumulating evidence indicates that dysregulation of OPA1 expression or activity contributes to the initiation and progression of multiple malignancies, underscoring its importance in tumor cell survival, proliferation, metabolic adaptation, and resistance to stress. Here, we summarize current knowledge on OPA1 dysregulation in cancer and, based on preliminary, unpublished in silico analyses, we highlight the growing relevance of OPA1 as a therapeutic target, particularly through its GTPase domain and the still understudied Interface 7. Overall, these findings outline how integrated computational approaches could potentially guide the identification of novel OPA1 modulators, offering a conceptual framework that highlights OPA1 as a promising, yet still largely underexplored, target in oncology. Full article