Search Results (1,299)

Manganese (Mn) is an essential trace element and a cofactor for several key enzymes, such as mitochondrial superoxide dismutase. Consequently, it plays an important defense role against reactive oxygen species. Despite this, Mn chronic overexposure can result in a neurological disorder referred to as manganism, which shares some similarities with Parkinson’s disease. Mn levels seem regulated by many transporters responsible for its uptake and efflux. These transporters play an established role in many inherited disorders of Mn metabolism and neurotoxicity. Some inherited Mn metabolism disorders, caused by mutations of SLC30A10 and SLC39A14, assume crucial importance since earlier treatment results in a better prognosis. Physicians should be familiar with the clinical presentation of these disorders as the underlying cause of dystonia/parkinsonism and look for other accompanying features, such as liver disease and polycythemia, which are typically associated with SLC30A10 mutations. This review aims to highlight the currently known Mn transporters, Mn-related neurotoxicity, and its consequences, and it provides an overview of inherited and acquired disorders of Mn metabolism. Currently available treatments are also discussed, focusing on the most frequently encountered presentations. Full article

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) preserve cardiac and renal function by mechanisms that are not completely elucidated. Among other things, SGLT2i promote nutrient-deprivation signalling, which might affect the immune function. As the fate of immune cells is controlled by their metabolism, we aimed to study the mitochondrial integrity of lymphocytes isolated from renal transplant recipients with type 2 diabetes (T2D) upon SGLT2i therapy instauration and six-month follow up. In this real-world pilot study, the mitochondrial respiration of isolated peripheral blood mononuclear cells was monitored in a Seahorse XFp extracellular-flux analyzer and cells were photographed with a confocal microscope. Mitochondrial mass, membrane potential, and superoxide content of lymphocyte subpopulations were measured by flow cytometry (MitoTracker^TM Green, TMRM, and MitoSOX^TM Red probes). Leveraging in vivo conditions of immune cells, we evaluated their metabolic profiles associated with immune activation. Herein, we identified changes in redox homeostasis with sustained membrane polarization, and an increased mitochondrial biogenesis upon PHA stimulation that significantly correlated with changes in body weight and LDL-cholesterol levels, and a resultant compensatory mitochondrial function of lymphocytes. Our data suggest novel mechanisms induced by SGLT2i to modulate immune cells, which probably underlie the observed beneficial effects in kidney transplant recipients. Nonetheless, further mechanistic studies are required to extend these exploratory findings and encourage the use of this therapeutic strategy. Full article

For nearly three decades, interspecies somatic cell nuclear transfer (iSCNT) has been explored as a potential tool for cloning, regenerative medicine, and wildlife conservation. However, developmental inefficiencies remain a major challenge, largely due to persistent barriers in nucleocytoplasmic transport, mitonuclear communication, and epigenome crosstalk. This review synthesized peer-reviewed English articles from PubMed, Web of Science, and Scopus, spanning nearly three decades, using relevant keywords to explore the molecular mechanisms underlying iSCNT inefficiencies and potential improvement strategies. We highlight recent findings deepening the understanding of interspecies barriers in iSCNT, emphasizing their interconnected complexities, including the following: (1) nucleocytoplasmic incompatibility may disrupt nuclear pore complex (NPC) assembly and maturation, impairing the nuclear transport of essential transcription factors (TFs), embryonic genome activation (EGA), and nuclear reprogramming; (2) mitonuclear incompatibility could lead to nuclear and mitochondrial DNA (nDNA-mtDNA) mismatches, affecting electron transport chain (ETC) assembly, oxidative phosphorylation, and energy metabolism; (3) these interrelated incompatibilities can further influence epigenetic regulation, potentially leading to incomplete epigenetic reprogramming in iSCNT embryos. Addressing these challenges requires a multifaceted, species-specific approach that balances multiple incompatibilities rather than isolating a single factor. Gaining insight into the molecular interactions between the donor nucleus and recipient cytoplast, coupled with optimizing strategies tailored to specific pairings, could significantly enhance iSCNT efficiency, ultimately transforming experimental breakthroughs into real-world applications in reproductive biotechnology, regenerative medicine, and species conservation. Full article

HIV-associated neurocognitive disorders are prevalent despite antiretroviral intervention. Some HIV virotoxins, such as the trans-activator of transcription (Tat), are not targeted by antiretrovirals, and their neurotoxic actions may be exacerbated by opioids. Both Tat and morphine disrupt mitochondrial function, which may promote neurotoxicity, but the mechanisms are poorly understood. Herein, we assess the capacity of HIV Tat and morphine to alter the fundamental ability of mitochondria to generate and transfer energy along the electron transport chain (ETC). We find that exposure to Tat inhibits mitochondrial respiration driven by ETC complexes I or II in a concentration-dependent manner. Findings were consistent across models of permeabilized neuroblastoma cells, murine-derived mitoplasts, and mitochondria derived from mice exposed to Tat in vivo. In cell culture models, Tat promoted Ca²⁺ influx and the generation of cytosolic reactive oxygen species (ROS). Acute exposure to morphine exerted no effect on mitochondrial respiration, but morphine modestly offset Tat-mediated effects on complex I and some effects for the generation of ROS. Morphine did not exert any protective effects when acutely administered in vivo. The mitoprotective steroid, allopregnanolone (AlloP), increased mitochondrial respiration in neuroblastoma cells (complex I) or mitoplasts (complex II) and attenuated Tat-mediated impairment of complexes I and II in neuroblastoma cells or mice exposed to Tat in vivo. AlloP further attenuated Tat-mediated intracellular Ca²⁺ influx and cytosolic ROS production. Taken together, these results suggest that HIV Tat compromises mitochondrial function through the impairment of respiratory complexes I and II and that physiological AlloP may exert protective effects. Full article

Background: Heart failure (HF), the terminal stage of cardiovascular disease with high morbidity and mortality, remains poorly managed by current therapies. Ventricular remodeling in HF is fundamentally characterized by myocardial fibrosis. While ginsenoside Rb₁ has demonstrated anti-fibrotic effects in HF, the underlying mechanism remains unclear. Twist1, an upstream regulator of energy metabolism factors PGC-1α and PPARα, may attenuate fibrosis by preserving systemic energy homeostasis, suggesting its pivotal role in HF pathogenesis. This study explores ginsenoside Rb₁′s anti-HF mechanisms through the regulation of ginsenoside Rb₁ on these metabolic regulators. Methods: Sprague Dawley rats were subjected to a ligation of the left anterior descending coronary artery to induce an HF model, followed by ginsenoside Rb₁ treatment for 6 weeks. Therapeutic effects were evaluated through cardiac function assessment, myocardial histopathological staining (HE, Masson, immunofluorescence, immunohistochemistry), mitochondrial morphology observation (transmission electron microscopy), energy metabolism analysis (electron transport chain efficiency, mitochondrial membrane potential, ATP content), and protein expression profiling (Twist1, PGC-1α, PPARα, GLUT4, PPARγ). Additionally, H9c2 cells induced with endothelin-1 to model HF were employed as an in vitro model to further investigate ginsenoside Rb₁′s regulatory effects on the Twist1/PGC-1α/PPARα signaling pathway. Results: Ginsenoside Rb₁ can restore cardiac function in HF rats, improve mitochondrial function, alleviate energy metabolism disorders, and inhibit ventricular remodeling. By modulating the Twist1/PGC-1α/PPARα signaling pathway, ginsenoside Rb₁ suppressed the abnormal overexpression of Twist1 and maintained normal expression of downstream PGC-1α and PPARα. In vitro experiments further demonstrated that ginsenoside Rb₁ significantly inhibited Twist1 expression in H9c2 cardiomyocytes with HF while promoting PGC-1α and PPARα expression, thereby restoring myocardial energy metabolism and mitigating ventricular remodeling in HF. Conclusions: Ginsenoside Rb₁ can inhibit the upregulation of Twist1 and activate the expression of its downstream PGC-1α and PPARα expression, by modulating the Twist1/PGC-1α/PPARα signaling pathway, alleviating ventricular remodeling in HF patients and improving myocardial energy metabolism dysfunction. Twist1 may be a key target for the treatment of HF. This study not only elucidates the mechanism by which ginsenoside Rb₁ alleviates HF, but also provides new insights into the clinical treatment of HF. Full article

Diabetes mellitus is characterized by a state of hyperglycemia, which can lead to severe complications if left untreated or poorly managed. Diabetic peripheral neuropathy (DPN) is one common complication. This condition is characterized by damage to the nerves that supply the legs and feet as well as problems with blood vessels, the heart, or urinary tract. To alleviate pain for patients, clinicians resort to long-term treatment regimens of nerve pain medications, which are usually either anticonvulsants or antidepressants. However, little is understood about the underlying mechanisms of DPN. Many pathogenic pathways have been proposed, one of which is mitochondrial dysfunction. Mitochondrial dysfunction includes a range of possible deficiencies given the number of functions controlled by or located in mitochondria, including their core function of bioenergetics. This review focuses on mitochondrial bioenergetics, including respiration/ATP synthesis and reactive oxygen species (ROS) production, as well as calcium homeostasis and apoptosis, and their potential as targets for the effective treatment of diabetic peripheral neuropathy. Full article

Triple-negative breast cancer (TNBC) presents a significant therapeutic challenge due to the absence of specific targeted treatments. In this study, we explored the therapeutic potential of xanthocillin X dimethyl ether (XanDME), a naturally occurring isocyanide isolated from the marine fungus Scedosporium apiospermum, on TNBC. To elucidate the underlying mechanism, we initially demonstrated that XanDME directly binds to hemin, the oxidized form of heme, in vitro, corroborating previous reports. This interaction led to the depletion of intracellular regulatory heme. We further established that XanDME translocates into the mitochondria, where it interacts with crucial hemoproteins, namely cytochromes. The binding of XanDME with mitochondrial cytochromes disrupts the electron transport chain (ETC), inhibits the activity of mitochondrial complexes, and inactivates mitochondrial respiration. The inhibitory activity of XanDME on mitochondrial function significantly contributes to its anti-TNBC effects, as observed both in vitro and in vivo. Our study underscores the potential of XanDME against TNBC, warranting further investigations. Full article

Solute carrier family 25 member A22 (SLC25A22) is a glutamate transporter in the inner mitochondrial membrane that is known to suppress ferroptosis in pancreatic ductal adenocarcinoma (PDAC). Sirtuin 3 (SIRT3) is the main mitochondrial deacetylase, and we previously demonstrated that targeting SIRT3 sensitized glioblastoma to ferroptosis by promoting mitophagy and inhibiting SLC7A11. The purpose of this study was to analyze the effect of SIRT3-mediated deacetylation of mitochondrial SLC25A22 on RAS-selective lethal 3 (RSL3)-induced ferroptosis in lung adenocarcinoma (LUAD). We found that the expression of SLC25A22 and SIRT3 had a high positive correlation and that their expression was greater in LUAD tissues than in adjacent tissues. The RSL3-induced ferroptosis of LUAD led to upregulation of SLC25A22 and SIRT3, and SIRT3 protected RSL3-induced LUAD from ferroptosis in vitro and in vivo. At the molecular level, SIRT3 bound with SLC25A22 and deacetylated this protein. Targeting SIRT3 enhanced the acetylation of SLC25A22, decreased its ubiquitination, and promoted 26S proteasome degradation in LUAD cells. Therefore, our results demonstrated that SIRT3 protected LUAD cells from RSL3-induced ferroptosis, and this effect is at least partially due to its deacetylation of SLC25A22, revealing that the SIRT3-SLC25A22 axis has an important role in regulating the ferroptosis of LUAD cells. Full article

The neurotoxicity of phosphorylated tau protein (P-tau) and mitochondrial dysfunction play a significant role in the pathophysiology of Alzheimer’s disease (AD). In vitro studies of the effects of P-tau oligomers on mitochondrial bioenergetics and reactive oxygen species production will allow us to evaluate the direct influence of P-tau on mitochondrial function. We measured the in vitro effect of P-tau oligomers on oxygen consumption and hydrogen peroxide production in isolated brain mitochondria. An appropriate combination of specific substrates and inhibitors of the phosphorylation pathway enabled the measurement and functional analysis of the effect of P-tau on mitochondrial respiration in defined coupling control states achieved in complex I-, II-, and I&II-linked electron transfer pathways. At submicromolar P-tau concentrations, we found no significant effect of P-tau on either mitochondrial respiration or hydrogen peroxide production in different respiratory states. The titration of P-tau showed a nonsignificant dose-dependent decrease in hydrogen peroxide production for complex I- and I&II-linked pathways. An insignificant in vitro effect of P-tau oligomers on both mitochondrial respiration and hydrogen peroxide production indicates that P-tau-induced mitochondrial dysfunction in AD is not due to direct effects of P-tau on the efficiency of the electron transport chain and on the production of reactive oxygen species. Full article

Membrane contact sites (MCSs) between the endoplasmic reticulum and the plasma membrane enable the transport of lipids without membrane fusion. Extended Synaptotagmins (ESYTs) act at MCSs, functioning as tethers between two membrane compartments. In plants, ESYTs have been mainly investigated in A. thaliana and shown to maintain the integrity of the plasma membrane, especially during stress responses like cold acclimatization, mechanical trauma, and salt stress. ESYTs are present at the MCSs of plasmodesmata, where they regulate defense responses by modulating cell-to-cell transfer of pathogens. Here, the analysis of ESYTs was expanded to the bryophyte Physcomitrium patens, an extant representative of the earliest land plant lineages. P. patens was found to contain a large number of ESYTs, distributed over all previously established classes and an additional class not present in A. thaliana. Motif discovery identified regions in the Synaptotagmin-like mitochondrial (SMP) domain that may explain phylogenetic relationships as well as protein function. The adaptation mechanisms of P. patens necessary to conquer land and its simple tissue structure make it highly suitable as a model organism to study ESYT functions in tip growth, stress responses, and plasmodesmata-mediated transport, and open new directions of research regarding the function of MCSs in cellular processes and plant evolution. Full article

Intrauterine growth restriction (IUGR) affects 5–10% of pregnancies with placental hypoxia, playing a key role as a common pathophysiological pathway of different etiologies. Despite the high metabolic rate of the placenta and its “gatekeeper” role in protecting the fetus from hypoxia, the response of placental mitochondria to hypoxic stress is not well understood. This study tested the hypothesis that transient exposure to hypoxia leads to a loss of placental mitochondria and affects their function. Human villous trophoblastic (JEG-3) cells were cultured under normoxic and hypoxic conditions for 24 h. Mitochondrial content was determined by flow cytometry before and after hypoxic exposure and after 24 h of normoxic recovery. Parameters of oxidative phosphorylation were assessed using a respirometric analyzer before hypoxic exposure and after normoxic recovery. Mitochondrial content decreased significantly from 88.5% to 26.7% during hypoxic incubation. Although it had increased to 84.2% after 24 h of normoxic recovery, oxidative phosphorylation parameters were still significantly suppressed to 1/2 to 1/3 of the pre-incubation levels. The results underscore the ability of placental cells to adapt mitochondrial content to O₂ supply. Despite rapid recovery under normoxia, respiratory function remains suppressed, which may result in persistent impairment of adenosine triphosphate (ATP)-dependent synthetic and transport functions. Full article

The silkworm is a species within the order Lepidoptera and an economic insect. The nutrients are obtained from the leaf and utilized by the silkworm larvae for body growth, development, and cocoon formation. Protein plays a significant functional role in the diet of silkworms. To investigate the impact of the high-protein diet (HPD 6%) on silkworm growth and development, transcriptomic analysis was conducted on the silkworm midgut, and 1724 differentially expressed genes (DEGs) were identified, comprising 803 up-regulated genes and 921 down-regulated genes. The up-regulated genes exhibited the majority pathway of mitochondrial oxidative phosphorylation, ribosome, and ribosome biogenesis in eukaryotes. The down-regulated genes of DEGs were mostly annotated in ABC transporters, lysosome, endocytosis, and sphingolipid metabolism pathways. The comprehensive analysis of DEGs indicated that substantial modifications were observed in various pathways associated with crucial biological processes. HPD 6% decreased oxidative stress and increased mitochondrial activity, ribosomal activity, and DNA repair capacity. Additionally, the ATP levels were increased in the midgut, malpighian tubule, middle silk gland, and posterior silk gland of the HPD 6% group. Moreover, the activities of SOD and NADH were enhanced in the midgut of the HPD 6% group. Our findings provide valuable insights into the wide-ranging effects of an HPD treatment in insects such as silkworms. Full article

The heart requires a continuous energy supply to sustain its unceasing contraction–relaxation cycle. Mitochondria, a double-membrane organelle, generate approximately 90% of cellular energy as adenosine triphosphate (ATP) through oxidative phosphorylation, utilizing the electrochemical gradient established by the respiratory chain. Mitochondrial function is compromised by damage to mitochondrial DNA, including point mutations, deletions, duplications, or inversions. Additionally, disruptions to proteins associated with mitochondrial membranes regulating metabolic homeostasis can impair the respiratory chain’s efficiency. This results in diminished ATP production and increased generation of reactive oxygen species. This review provides an overview of mutations affecting mitochondrial transporters and proteins involved in mitochondrial energy synthesis, particularly those involved in ATP synthesis and mobilization, and it examines their role in the pathogenesis of specific cardiomyopathies. Full article

Delayed reperfusion of the ischemic heart (I/R) is known to impair the recovery of cardiac function and produce a wide variety of myocardial defects, including ultrastructural damage, metabolic alterations, subcellular Ca²⁺-handling abnormalities, activation of proteases, and changes in cardiac gene expression. Although I/R injury has been reported to induce the formation of reactive oxygen species (ROS), inflammation, and intracellular Ca²⁺ overload, the generation of oxidative stress is considered to play a critical role in the development of cardiac dysfunction. Increases in the production of superoxide, hydroxyl radicals, and oxidants, such as hydrogen peroxide and hypochlorous acid, occur in hearts subjected to I/R injury. In fact, mitochondria are a major source of the excessive production of ROS in I/R hearts due to impairment in the electron transport system as well as activation of xanthine oxidase and NADPH oxidase. Nitric oxide synthase, mainly present in the endothelium, is also activated due to I/R injury, leading to the production of nitric oxide, which, upon combination with superoxide radicals, generates nitrosative stress. Alterations in cardiac function, sarcolemma, sarcoplasmic reticulum Ca²⁺-handling activities, mitochondrial oxidative phosphorylation, and protease activation due to I/R injury are simulated upon exposing the heart to the oxyradical-generating system (xanthine plus xanthine oxidase) or H₂O₂. On the other hand, the activation of endogenous antioxidants such as superoxide dismutase, catalase, glutathione peroxidase, and the concentration of a transcription factor (Nrf2), which modulates the expression of various endogenous antioxidants, is depressed due to I/R injury in hearts. Furthermore, pretreatment of hearts with antioxidants such as catalase plus superoxide dismutase, N-acetylcysteine, and mercaptopropionylglycerine has been observed to attenuate I/R-induced subcellular Ca²⁺ handling and changes in Ca²⁺-regulatory activities; additionally, it has been found to depress protease activation and improve the recovery of cardiac function. These observations indicate that oxidative stress is intimately involved in the pathological effects of I/R injury and different antioxidants attenuate I/R-induced subcellular alterations and improve the recovery of cardiac function. Thus, we are faced with the task of developing safe and effective antioxidants as well as agents for upregulating the expression of endogenous antioxidants for the therapy of I/R injury. Full article

Drug-resistant epilepsy (DRE) affects 20–30% of patients with epilepsy who fail to achieve seizure control with antiseizure medications, posing a significant therapeutic challenge. In this narrative review, we examine the clinical efficacy and safety of the classic ketogenic diet (cKD) and its variants, including the modified Atkins diet (MAD), medium-chain triglyceride diet (MCTD), and low glycemic index treatment (LGIT), in patients with genetically confirmed drug-resistant epilepsy. These diets induce a metabolic shift from glucose to ketones, enhance mitochondrial function, modulate neurotransmitter balance, and exert anti-inflammatory effects. However, genetic factors strongly influence the efficacy and safety of the cKD, with absolute indications including glucose transporter type 1 deficiency syndrome (GLUT1DS) and pyruvate dehydrogenase complex deficiency (PDCD). Preferred adjunctive applications of the KD include genetic epilepsies, such as SCN1A-related Dravet syndrome, TSC1/TSC2-related tuberous sclerosis complex, and UBE3A-related Angelman syndrome. However, because of the risk of metabolic decompensation, the cKD is contraindicated in patients with pathogenic variants of pyruvate carboxylase and SLC22A5. Recent advancements in precision medicine suggest that genetic and microbiome profiling may refine patient selection and optimize KD-based dietary interventions. Genome-wide association studies and multiomics approaches have identified key metabolic pathways influencing the response to the cKD, and these pave the way for individualized treatment strategies. Future research should integrate genomic, metabolomic, and microbiome data to develop biomarker-driven dietary protocols with improved efficacy and safety. As dietary therapies continue to evolve, a personalized medical approach is essential to maximize their clinical utility for genetic epilepsy and refractory epilepsy syndromes. Full article