Neuropathic pain is a chronic and devastating clinical problem with few effective treatments. Mitochondrial dysfunction plays a critical role in the pathological process of neuropathic pain. Recently, mitochondrial calcium overload has been identified as the initial part of mitochondrial dysfunction, such as dynamic imbalance and excessive superoxide. Mitochondrial Ca2+ uniporter (MCU) serves as the primary channel for mitochondrial Ca2+ uptake, and Na+/Ca2+ exchanger (NCLX) is the dominant mechanism for mitochondrial calcium ion excretion. Herein, we investigated the role of mitochondrial calcium overload and its regulated channels in a rat model of neuropathic pain. Our results showed significant mitochondrial calcium overload in the spinal dorsal horn of SNI rats, accompanied by the upregulation of MCU and downregulation of NCLX. MCU inhibition or NCLX overexpression remarkably relieved mechanical allodynia and mitochondrial high calcium levels in SNI rats. Conversely, upregulation of MCU or downregulation of NCLX induced mitochondrial calcium overload and mechanical allodynia in naïve rats. We also observed excessive mitochondrial fission and reduced fusion in the spinal cord of SNI rats, which could be mitigated by MCU inhibition and NCLX overexpression, respectively. Notably, mitochondrial fission inhibitor or mitochondrial fusion promoter effectively reversed the MCU overexpression or NCLX knockdown-induced mechanical allodynia. Collectively, our data indicate that the MCU/NCLX-mediated mitochondrial calcium overload drives excessive mitochondrial fission, which promotes the progression of SNI.

Drought significantly restricts the growth and quality of fruit trees Prunus mira, an ancient wild peach species, exhibits strong drought tolerance; however, the detailed response mechanism remains unknown. The nucleic acid excision repair factor radiation sensitivity 23d (Rad23d) plays a crucial role in plant stress, growth, and development. However, its specific mechanism of action in P. mira is unclear. Here, we report that PmRad23d positively contributes to the abscisic acid (ABA)-dependent drought response in P. mira. Overexpression of PmRad23d enhanced drought tolerance and ABA sensitivity, whereas inhibiting PmRad23d expression reduced the plant's drought tolerance and ABA sensitivity. PmRad23d was found to interact with the C2 domain at the N-terminus of PmSRC2 and PmCAR4, respectively. Together, they regulate the expression of ABA- and drought-related genes, activate ABA signaling, and induce stomatal closure, ultimately enhancing drought resistance in plants. Our findings shed light on the ABA-dependent drought response mechanism of PmRad23d, providing a basis for further exploration of drought tolerance in P. mira. Additionally, this study identifies potential candidate genes for enhancing peach germplasm resources and breeding drought-tolerant cultivars.

LMNA mutation related Emery-Dreifuss muscular dystrophy (LMNA-related EDMD), is a rare genetic disorder often involving life-threatening cardiac complications. However, the molecular links between LMNA mutations and their related EDMD cardiac phenotypes have remained unclear. Here, using EDMD patient-specific and genome-edited induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we link the LMNA L204P mutation with the pathogenic phenotypes of arrhythmia and contractile dysfunction. Using multi-omics analysis, we then show that LMNA L204P results in decreased chromatin accessibility, leading to the downregulation of JAK2 in EDMD iPSC-CMs. Mechanistically, JAK2/STAT3 signaling pathway suppression in EDMD iPSC-CMs is shown to cause mitochondrial dysfunction and oxidative stress, ultimately resulting in the above phenotypes. Conversely, pharmacological or genetic activation of JAK2/STAT3 signaling effectively rescues both the arrhythmic and contractile dysfunction phenotypes in EDMD iPSC-CMs via improvements in mitochondrial function. In addition, whilst EDMD engineered heart tissues (EHTs) display dysfunctional contractile force generation, this can also be significantly alleviated by STAT3 activation. Taken together, we present chromatin compartment change-mediated JAK2/STAT3 suppression as a novel mechanism underlying cardiac pathogenic phenotypes in LMNA-related EDMD. Our findings indicate that activating the JAK2/STAT3 signaling pathway may hold the potential to serve as a novel therapeutic strategy for this condition.

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and impaired metabolic efficiency. This study investigates the therapeutic potential of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin (EMPA) in ameliorating these pathological features in a mouse model carrying the myosin R403Q mutation.

Male mice harbouring the R403Q mutation were treated with EMPA for 16 weeks. Multi-nuclear magnetic resonance spectroscopy (31P, 13C, and 23Na MRS), echocardiography, transcriptomic, proteomic, and phosphoproteomic profiling were utilized to assess metabolic, structural, and functional changes.

Empagliflozin facilitated the coupling of glycolysis with glucose oxidation and normalized elevated intracellular sodium levels. Treatment resulted in a significant reduction in LVH and myocardial fibrosis as evidenced by echocardiography and histopathology. These structural improvements correlated with enhancements in mitochondrial adenosine triphosphate (ATP) synthesis, fatty acid oxidation, and branched-chain amino acid catabolism. Furthermore, EMPA improved left ventricular diastolic function and contractile reserve, underscored by improved ATP production and reduced energy cost of contraction. Notably, these benefits were linked to down-regulation of the mammalian target of rapamycin signalling pathway and normalization of myocardial substrate metabolic fluxes.

Empagliflozin significantly mitigates structural and metabolic dysfunctions in a mouse model of HCM, underscoring its potential as a therapeutic agent for managing this condition. These findings suggest broader applicability of SGLT2i in cardiovascular diseases, including those due to myocardial-specific mutations, warranting further clinical investigation.

As a promising neural stimulation technique, infrared neural stimulation (INS) has recently gained significant attention due to its ability to stimulate neuronal activities without needing exogenous agents. NIR light is absorbed by water of the tissue producing local thermal effects. Therefore, INS is a suitable candidate for localized and targeted neural stimulation. However, despite the wide variety of research studies on INS applications, limited studies have focused on identifying and optimizing the stimulation parameters to avoid potential excitotoxicity. This study evaluates the dorsal root ganglia (DRG) neurons' response under INS with varying intensities and illumination time.

Here, DRG neurons are cultured and labeled by the CamkII-GCaMP6s virus. The neurons were exposed to infrared laser pulses (2.01 µm wavelength, different powers of 2.5 mW, 5 mW, 7.5 mW, and 10 mW) for durations of 300 s and 400 s. The light was delivered through a silica optical fiber aligned and stabilized within a free-space optical setup. Simultaneous with INS, neuronal activity was evaluated by calcium imaging through a fluorescence microscope. This method allowed real-time monitoring of neuronal calcium dynamics under different stimulation conditions, preparing an overview of the safe thresholds for INS.

It was found that calcium saturation has happened for the neurons in exposure to light intensities (7.5 mW and 10 mW) for 300 s, representing potential excitotoxicity. In contrast, with the same exposure time, lower light intensities (2.5 mW and 5 mW) did not show significant signs of calcium saturation or neuronal damage. Moreover, in some neuronal networks, the peripheral neurons of the illuminated area revealed indirect activation, indicating inter-neuronal communication effects.

Compared to previous studies that have explored the use of INS on DRG neurons, our work introduces a systematic approach to evaluate the light intensity-dependent INS, while addressing the critical issue of potential thermal injury. While earlier research has demonstrated the ability of INS to modulate neuronal activity and reduce electrical artifacts in electrophysiological recordings, concerns regarding excitotoxicity and neuronal damage remain insufficiently investigated. We examined a range of laser intensities (2.5 mW to 10 mW) to determine the safe exposure thresholds and optimize the photothermal impact. Furthermore, by utilizing CamKII-GCaMP6s virus-modified neurons, we enhance sensitivity in detecting calcium influx, providing a more precise evaluation of neuronal responses to INS. Therefore, here, we provide the knowledge for safe INS.

This work identifies the required laser stimulation parameters, particularly intensity and illumination time of the tissue for efficient and safe INS. We concluded that higher intensities (7.5 mW and 10 mW) can cause calcium saturation and potential neuronal injury, while lower intensities (2.5 mW and 5 mW) are safe for prolonged exposure. Moreover, the observed peripheral neuronal activation suggests indirect stimulation through inter-neuronal connections, offering further insights into the effects of INS on neural networks. These findings contribute valuable information towards safe neuromodulation methods with potential use in clinical settings.

Mitochondrial reactive oxygen species (mROS) are generated as byproducts of mitochondrial oxidative phosphorylation. Changes in mROS levels are involved in tumorigenesis through their effects on cancer genome instability, sustained cancer cell survival, metabolic reprogramming, and tumor metastasis. Recent advances in nanotechnology offer a promising approach for precise regulation of mROS by either enhancing or depleting mROS generation. This review examines the association between dysregulated mROS levels and key cancer hallmarks. We also discuss the potential applications of mROS-targeted nanoparticles that artificially manipulate ROS levels in the mitochondria to achieve precise delivery of antitumor drugs.

Clinical management of heart failure with preserved ejection fraction (HFpEF) is hindered by a lack of disease-modifying therapies capable of altering its distinct pathophysiology. Despite the widespread implementation of a 2-hit model of cardiometabolic HFpEF to inform precision therapy, which utilizes ad libitum high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester, we observe that C57BL6/J mice exhibit less cardiac diastolic dysfunction in response to high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester.

Genetic strain-specific single-nucleus transcriptomic analysis identified disease-relevant genes that enrich oxidative metabolic pathways within cardiomyocytes. Because C57BL/6J mice are known to harbor a loss-of-function mutation affecting the inner mitochondrial membrane protein Nnt (nicotinamide nucleotide transhydrogenase), we used an isogenic model of Nnt loss-of-function to determine whether intact NNT is necessary for the pathological cardiac manifestations of high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester. Twelve-week-old mice cross-bred to isolate wild-type (Nnt+/+) or loss-of-function (Nnt-/-) Nnt in the C57BL/6N background were challenged with high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester for 9 weeks (n=6-10).

Nnt+/+ mice exhibited impaired ventricular diastolic relaxation and pathological remodeling, as assessed via E/e' (42.8 versus 21.5, P=1.2×10-10), E/A (2.3 versus 1.4, P=4.1×10-2), diastolic stiffness (0.09 versus 0.04 mm Hg/μL, P=5.1×10-3), and myocardial fibrosis (P=2.3×10-2). Liquid chromatography and mass spectroscopy exposed a 40.0% reduction in NAD+ (P=8.4×10-3) and a 38.8% reduction in glutathione:GSSG (P=2.6×10-2) among Nnt+/+ mice after high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester feeding. Using single-nucleus ligand-receptor analysis, we implicate Fgf1 (fibroblast growth factor 1) as a putative NNT-dependent mediator of cardiomyocyte-to-fibroblast signaling of myocardial fibrosis.

Together, these findings underscore the pivotal role of mitochondrial dysfunction in HFpEF pathogenesis, implicating both NNT and Fgf1 as novel therapeutic targets.

Triterpenoids are the bioactive components in Inonotus obliquus with extensive medicinal prospects, but their low content in fermentation production is the main limiting factor for their application. This study focuses on nitric oxide (NO), an important signaling molecule within organisms, aiming to explore its inducing effect on the synthesis of triterpenes in I. obliquus and the potential signaling transduction mechanisms involved. Compared with the control group, the content of representative triterpenoid betulin increased by 70.59% after adding the NO donor sodium nitroprusside. Gene expression level detection revealed that NO mainly promotes its biosynthesis by activating the transcription of key enzyme genes in the downstream pathway of betulin biosynthesis, thereby increasing its abundance. Tracing upstream, the NO signal was found to induce the upregulation of genes related to cellular antioxidant and calcium ion signaling pathways. Notably, IoCAMP responded strongly to the NO signal, participating in the regulation of cytoplasmic Ca2+ concentration by altering the Ca2+ concentration of mitochondria together with IoCATP and IoCALM. Additionally, the signaling of changes in Ca2+ concentrations is likely to crosstalk with the reactive oxygen species (ROS) signaling pathway. The increase in enzyme activity of IoNOX after NO induction confirmed the activation of the ROS signaling pathway. It works in synergy with IoSOD and IoCAT to reduce oxidative damage and promote downstream triterpenoid biosynthesis. This study not only contributes to clarify the signaling pathways regulating NO-mediated triterpenoid biosynthesis but also provides a theoretical basis for the efficient production of triterpenoid active components in I. obliquus.

Myocardial ischemia-reperfusion injury (MIRI) is fatal to patients, leading to cardiomyocyte death and myocardial remodeling. Reactive oxygen species (ROS) and oxidative stress play important roles in MIRI. There is a complex crosstalk between ROS and regulatory cell deaths (RCD) in cardiomyocytes, such as apoptosis, pyroptosis, autophagy, and ferroptosis. ROS is a double-edged sword. A reasonable level of ROS maintains the normal physiological activity of myocardial cells. However, during myocardial ischemia-reperfusion, excessive ROS generation accelerates myocardial damage through a variety of biological pathways. ROS regulates cardiomyocyte RCD through various molecular mechanisms. Targeting the removal of excess ROS has been considered an effective way to reverse myocardial damage. Many studies have applied antioxidant drugs or new advanced materials to reduce ROS levels to alleviate MIRI. Although the road from laboratory to clinic has been difficult, many scholars still persevere. This article reviews the molecular mechanisms of ROS inhibition to regulate cardiomyocyte RCD, with a view to providing new insights into prevention and treatment strategies for MIRI.

The incidence and hospitalization rate of kidney disease, especially end-stage renal disease, have increased significantly, which seriously endangers the health of patients. Mitochondria are the core organelles of cellular energy metabolism, and their dysfunction can lead to kidney energy supply insufficiency and oxidative stress damage, which has become a global public health problem. Studies have shown that the disturbance of mitochondrial quality control mechanisms, including mitochondrial dynamics, autophagy, oxidative stress regulation and biosynthesis, is closely related to the occurrence and development of renal fibrosis (RF). As a multicellular pathological process, RF involves the injury and shedding of podocytes, the transdifferentiation of renal tubular epithelial cells, the activation of fibroblasts, and the infiltration of macrophages, among which the mitochondrial dysfunction plays an important role. This review systematically elaborates the molecular mechanisms of mitochondrial damage during RF progression, aiming to provide theoretical foundations for developing novel therapeutic strategies to delay RF advancement.

Heart failure (HF) has emerged as one of the foremost global health threats due to its intricate pathophysiological mechanisms and multifactorial etiology. Adenosine triphosphate (ATP)-induced cell death represents a novel form of regulated cell deaths, marked by cellular energy depletion and metabolic dysregulation stemming from excessive ATP accumulation, identifying its uniqueness compared to other cell death processes modalities such as programmed cell death and necrosis. Growing evidence suggests that ATP-induced cell death (AICD) is predominantly governed by various biological pathways, including energy metabolism, redox homeostasis and intracellular calcium equilibrium. Recent research has shown that AICD is crucial in HF induced by pathological conditions like myocardial infarction, ischemia-reperfusion injury, and chemotherapy. Thus, it is essential to investigate the function of AICD in the pathogenesis of HF, as this may provide a foundation for the development of targeted therapies and novel treatment strategies. This review synthesizes current advancements in understanding the link between AICD and HF, while further elucidating its involvement in cardiac remodeling and HF progression.

Mitochondrial dysfunction fuels vascular inflammation and atherosclerosis. Mitochondrial calcium uptake 1 (MICU1) maintains mitochondrial Ca2+ homeostasis. However, the role of MICU1 in vascular inflammation and atherosclerosis remains unknown. Here, we report that endothelial MICU1 prevents vascular inflammation and atherosclerosis by maintaining mitochondrial homeostasis. We observed that vascular inflammation was aggravated in endothelial cell-specific Micu1 knockout mice (Micu1ECKO) and attenuated in endothelial cell-specific Micu1 transgenic mice (Micu1ECTg). Furthermore, hypercholesterolemic Micu1ECKO mice also showed accelerated development of atherosclerosis, while Micu1ECTg mice were protected against atherosclerosis. Mechanistically, MICU1 depletion increased mitochondrial Ca2+ influx, thereby decreasing the expression of the mitochondrial deacetylase sirtuin 3 (SIRT3) and the ensuing deacetylation of superoxide dismutase 2 (SOD2), leading to the burst of mitochondrial reactive oxygen species (mROS). Of clinical relevance, we observed decreased MICU1 expression in the endothelial layer covering human atherosclerotic plaques and in human aortic endothelial cells exposed to serum from patients with coronary artery diseases (CAD). Two-sample Wald ratio Mendelian randomization further revealed that increased expression of MICU1 was associated with decreased risk of CAD and coronary artery bypass grafting (CABG). Our findings support MICU1 as an endogenous endothelial resilience factor that protects against vascular inflammation and atherosclerosis by maintaining mitochondrial Ca2+ homeostasis.

α-Hederin, a naturally occurring compound found in various plant sources, has remarkable properties and therapeutic potential for human health. One notable attribute is its potent anti-inflammatory activity, such as in arthritis, asthma, and inflammatory bowel disease. In addition, it exhibits notable antioxidant effects implicated in the development of chronic diseases, including cardiovascular disorders and certain types of cancer. According to research, it may limit the growth and proliferation of cancer cells, making it a possible candidate for future cancer treatments. Moreover, it is a promising neuroprotective agent and enhances cognitive function, suggesting its potential in the treatment of neurodegenerative illnesses like Alzheimer's and Parkinson's disease. The multifaceted benefits of α-hederin make it an intriguing compound with significant therapeutic implications. As research progresses, exploring its mechanisms of action and clinical applications is warranted. Harnessing the potential of α-hederin may pave the way for innovative treatment strategies and improved outcomes in the battle against various chronic diseases.

Regulation of mitochondrial Ca2+ uptake is critical in cardiac adaptation to chronic stressors. Abnormalities in Ca2+ handling, including mitochondrial uptake mechanisms, have been implicated in pathological heart hypertrophy. Enhancing mitochondrial Ca2+ uniporter (MCU) expression has been suggested to interfere with maladaptive development of heart failure. Here, we addressed whether MCU modulation affects the cardiac response to pressure overload. MCU content was quantified in human and murine hearts at different phases of myocardial hypertrophy. Cardiac function/structure were analyzed after Transverse Aortic Constriction (TAC) in mice undergone viral-assisted overexpression or downregulation of MCU. In vitro and ex vivo assays determined the effect of MCU modulation on mitochondrial Ca2+ uptake, cellular phenotype and hypertrophic signaling. In human and murine hearts MCU levels increased in the adaptive phase of myocardial hypertrophy and declined in the failing stage. Consistently, modulation of MCU had a cell-autonomous effect in cardiomyocyte/heart adaptation to chronic overload. Indeed, upon TAC MCU-downregulation accelerated development of contractile dysfunction, interstitial fibrosis and heart failure. Conversely, MCU-overexpression prolonged the adaptive phase of hypertrophic response, as, in advanced stages upon TAC, hearts showed preserved contractility, absence of fibrosis and intact vascularization. In vitro and ex vivo analyses indicated that enhancement in mitochondrial Ca2+ uptake in cardiomyocytes entails "mitochondrion-to-cytoplasm" signals leading to ROS-mediated activation of Akt, which may explain the protective effects towards heart response to TAC. Enhanced mitochondrial Ca2+ uptake affects the compensatory response to pressure overload via retrograde mitochondrial-Ca2+/ROS/Akt signaling, thus uncovering a potentially targetable mechanism against maladaptive myocardial hypertrophy.

Thiram, a broadly used dithiocarbamate fungicide, exaggerates endoplasmic reticulum (ER) stress and interferes with mitochondrial function, thus disrupting cellular homeostasis. Here, we intend to identify the molecular actions of thiram at the mitochondrial-associated ER membranes (MAMs) that lead to the induction of ER stress and mitochondrial calcium overload in both liver and bone tissues. Taken together, we show that thiram-induced remodelling of MAMs leads to huge ER stress and calcium dysregulation. Histological and immunohistochemical examinations revealed that thiram-induced hyperactivation of IP3R1 mediated the release of endoplasmic reticulum calcium, but mitochondrial calcium uptake was mediated by voltage-dependent anion channels VDAC1. This stress response was characterized by increased glucose regulated protein 78 (GRP78) expression in the liver and tibial growth plates (GP). In this respect, a new liver-bone axis was delineated for thiram-induced ER stress. More interestingly, the activation of NLRP3 inflammasome was very striking in tibial growth plates but not in liver tissues. Hence, the results highlight the systemic effects of thiram by identifying a critical metabolic junction that might play a role in metabolic disorders such as tibial dyschondroplasia and related bone disorders, e.g., osteoarthritis and osteoporosis.

This study aims to elucidate the potential impact of basal metabolic rate on ischemic stroke at the genetic prediction level through a two-sample Mendelian randomization analysis.

Using summary data from genome-wide association studies, we obtained information on basal metabolic rate and ischemic stroke from a large-scale genome-wide association study. MR analysis used inverse variance weighting, weighted median, MR-Egger, simple mode, and weighted estimation. Sensitivity analyses, including the MR-Egger method, MR-PRESSO, Cochran's Q-test, and leave-one-out assessment, were performed to assess the reliability of the results.

Genetic susceptibility to basal metabolic rate was significantly associated with ischemic stroke in multiple models, including the inverse variance weighting model (OR, 1.108 [95% CI: 1.005-1.221]; p = 0.0392), the weighted median method (OR, 1.179 [95% CI: 1.020-1.363]; p = 0.0263), and MR-Egger (OR, 1.291 [95% CI: 1.002-1.663]; p = 0.0491). These results indicate a positive causal relationship between basal metabolic rate and ischemic stroke. The MR-Egger intercept and Cochran's Q-test indicated the absence of heterogeneity and horizontal pleiotropy in the analyses of basal metabolic rate and ischemic stroke.

The MR analysis suggests a positive correlation between basal metabolic rate and ischemic stroke.

Aspartate (Asp) metabolism-mediated antioxidant functions have important implications for neonatal growth and intestinal health; however, the antioxidant mechanisms through which Asp regulates the gut microbiota and influences RIP activation remain elusive. This study reports that chronic oxidative stress disrupts gut microbiota and metabolite balance and that such imbalance is intricately tied to the perturbation of Asp metabolism. Under normal conditions, in vivo and in vitro studies reveal that exogenous Asp improves intestinal health by regulating epithelial cell proliferation, nutrient uptake, and apoptosis. During oxidative stress, Asp reduces Megasphaera abundance while increasing Ruminococcaceae. This reversal effect depends on the enhanced production of the antioxidant eicosapentaenoic acid mediated through Asp metabolism and microbiota. Mechanistically, the application of exogenous Asp orchestrates the antioxidant responses in enterocytes via the modulation of the RIP3-MLKL and RIP1-Nrf2-NF-κB pathways to eliminate excessive reactive oxygen species and maintain mitochondrial functionality and cellular survival. These results demonstrate that Asp signaling alleviates oxidative stress by dynamically modulating the gut microbiota and RIP-dependent mitochondrial function, providing a potential therapeutic strategy for oxidative stress disease treatment.

Atrial fibrillation (AF) is tightly linked to mitochondrial dysfunction, calcium (Ca²⁺) imbalance, and oxidative stress. Mitochondrial Ca²⁺ is essential for regulating metabolic enzymes, maintaining the tricarboxylic acid (TCA) cycle, supporting the electron transport chain (ETC), and producing ATP. Additionally, Ca²⁺ modulates oxidative balance by regulating antioxidant enzymes and reactive oxygen species (ROS) clearance. However, Ca²⁺ homeostasis disruptions, particularly overload, result in excessive ROS production, mitochondrial permeability transition pore (mPTP) opening, and oxidative stress-induced damage. These changes lead to mitochondrial dysfunction, Ca²⁺ leakage, and cardiomyocyte apoptosis, driving AF progression and atrial remodeling. Therapeutically, targeting mitochondrial Ca²⁺ homeostasis shows promise in mitigating AF. Moderate Ca²⁺ regulation enhances energy metabolism, stabilizes mitochondrial membrane potential, and bolsters antioxidant defenses by upregulating enzymes like superoxide dismutase and glutathione peroxidase. This reduces ROS generation and facilitates clearance. Proper Ca²⁺ levels also prevent electron leakage and promote mitophagy, aiding in damaged mitochondria removal and reducing ROS accumulation. Future strategies include modulating Ryanodine receptor 2 (RyR2), mitochondrial calcium uniporter (MCU), and sodium-calcium exchanger (NCLX) to control Ca²⁺ overload and oxidative damage. Addressing mitochondrial Ca²⁺ dynamics offers a compelling approach to breaking the cycle of Ca²⁺ overload, oxidative stress, and AF progression. Further research is needed to clarify the mechanisms of mitochondrial Ca²⁺ regulation and its role in AF pathogenesis. This knowledge will guide the development of innovative treatments to improve outcomes and quality of life for AF patients.

Glioblastoma (GBM) is the most common malignant tumour of the central nervous system. Despite recent advances in multimodal GBM therapy incorporating surgery, radiotherapy, systemic therapy (chemotherapy, targeted therapy), and supportive care, the overall survival (OS) remains poor, and long-term survival is rare. Currently, the primary obstacles hindering the effectiveness of GBM treatment are still the blood-brain barrier and tumor heterogeneity. In light of its substantial advantages over conventional therapies, such as strong penetrative ability and minimal side effects, low-frequency magnetic fields (LF-MFs) therapy has gradually caught the attention of scientists.

In this review, we shed the light on the current status of applying LF-MFs in the treatment of GBM. We specifically emphasize our current understanding of the mechanisms by which LF-MFs mediate anticancer effects and the challenges faced by LF-MFs in treating GBM cells. Furthermore, we discuss the prospective applications of magnetic field therapy in the future treatment of GBM. Key scientific concepts of review: The review explores the current progress on the use of LF-MFs in the treatment of GBM with a special focus on the potential underlying mechanisms of LF-MFs in anticancer effects. Additionally, we also discussed the complex magnetic field features and biological characteristics related to magnetic bioeffects. Finally, we proposed a promising magnetic field treatment strategy for future applications in GBM therapy.

Nucleoside diphosphate kinase B (NDPKB) deficiency in endothelial cells (ECs) promotes the activation of the hexosamine biosynthesis pathway (HBP), leading to vascular damage in the retina. The aim of this study was to investigate the consequences of NDPKB deficiency in the mouse heart.

NDPKB deficient mice were used in the study. Echocardiography was employed to assess cardiac function in vivo. Characterization of contractility in hiPSC-derived cardiomyocytes (hiPSC-CMs) was measured with the IonOptix contractility system. Immunoblotting and immunofluorescence were carried out to analyze the expression and localization of proteins in cultured cells and left ventricles (LVs).

NDPKB deficient mice displayed impaired glucose tolerance and increased heart weight compared to controls. Echocardiographic analysis revealed an increase in the diastolic diameter of the left ventricular posterior wall (LVPW), a decrease in the early diastolic mitral valve E and E' wave, and in the ratios of E/A and E'/A' in NDPKB deficient hearts, suggesting cardiac hypertrophy and diastolic dysfunction. In line with cardiac dysfunction, the phosphorylation of myocardial phospholamban (PLN) and the expression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) in the NDPKB deficient LVs were significantly reduced. Moreover, the accumulation of collagen, fibronectin as well as the upregulation of transforming growth factor β (TGF-β), were detected in NDPKB deficient LVs. In addition, activation of the HBP and its downstream O-GlcNAc cycle was observed in the LVs and cardiac ECs (CECs) isolated from the NDPKB-/- mice. Furthermore, a bipolar O-GlcNAc regulation was identified in CMs. O-GlcNAc was decreased in NDPKB-depleted CMs, while conditioned medium from NDPKB-depleted ECs significantly increased O-GlcNAc levels, along with contractile and relaxation dysfunction of the hiPSC-CMs, which was attenuated by inhibiting endothelial HBP activation.

Deficiency in NDPKB leads to endothelial activation of the HBP and cardiac dysfunction. Our findings may highlight the crucial role of proper endothelial HBP in maintaining cardiovascular homeostasis.

Myocardial ischemia-reperfusion injury (MIRI) often leads to irreversible myocardium dysfunction, while existing therapies are palliatives that transiently alleviate the disease symptoms. Repairing sarcoplasmic reticulum Ca2+-ATPase (SERCA) could reverse MIRI, which, however, requires precise drug delivery to the sarcoplasmic reticulum (SR). To this end, we leverage cell-cell "NETwork" of neutrophils to deliver SERCA activator-loaded SR-localized nanoparticles (L-P-NPs) to the damaged myocardial cells, following a hierarchical targeting process: (i) chemotactic neutrophils deliver L-P-NPs to ischemia-reperfused heart, achieving tissue level targeting; (ii) neutrophils produce neutrophil extracellular traps (NETs) to transport L-P-NPs to injured myocardial cell, achieving cellular level targeting; (iii) L-P-NPs escort therapeutic payloads to the SR, achieving subcellular targeting. We showed that this platform profoundly restored SERCA activity, augmented cardiac function, and ameliorated adverse heart remodeling. Our study provides insight into the direct restoration of SR for the effective treatment of MIRI and other muscle diseases.

Myocardial DNA damage plays a critical role in the pathogenesis of cardiovascular diseases, frequently leading to adverse outcomes such as myocardial infarction and heart failure. This study elucidated the protective effects of sodium alginate (SA) against myocardial DNA damage and explored the underlying molecular mechanisms involved. Hydrogen peroxide (H₂O₂) -stimulated AC16 cells were employed as an in vitro model to induce myocardial DNA damage, and CCK-8 assays established that SA exhibited no cytotoxicity at concentrations up to 800 µM. The protective effects of SA on myocardial DNA damage were shown to be mediated by VSNL1 using immunofluorescence, western blotting and qPCR analyses. To further substantiate this mechanism, lentiviral transduction was utilized to achieve VSNL1 overexpression, whereas targeted siRNA silencing was employed for VSNL1 knockdown. Following VSNL1 overexpression, a reduction in γ-H2AX protein expression was observed, accompanied by increased levels of CNP and NPR-B proteins on the cell membrane, as well as a decrease in intracellular calcium ion concentrations. Conversely, knockdown of VSNL1 reduced the protective effects of SA, highlighting its critical role in the mediation of cardioprotective mechanisms. Taken together, these findings suggest that SA exerts a potential protective effect against myocardial DNA damage through upregulating VSNL1, activating the CNP/NPR-B signaling pathway, and decreasing intracellular calcium ion accumulation. These results underscore that SA is a promising therapeutic candidate for the attenuation of myocardial injury.

Defects in chaperone-mediated autophagy (CMA) are associated with cellular senescence, but the mechanism remains poorly understood. Here, we found that CMA inhibition induced cellular senescence in a calcium-dependent manner and identified its role in TNF-induced senescence of nucleus pulposus cells (NPC) and intervertebral disc degeneration. Based on structural and functional proteomic screens, PLCG1 (phospholipase C gamma 1) was predicted as a potential substrate for CMA deficiency to affect calcium homeostasis. We further confirmed that PLCG1 was a key mediator of CMA in the regulation of intracellular calcium flux. Aberrant accumulation of PLCG1 caused by CMA blockage resulted in calcium overload, thereby inducing NPC senescence. Immunoassays on human specimens showed that reduced LAMP2A, the rate-limiting protein of CMA, or increased PLCG1 was associated with disc senescence, and the TNF-induced disc degeneration in rats was inhibited by overexpression of Lamp2a or knockdown of Plcg1. Because CMA dysregulation, calcium overload, and cellular senescence are common features of disc degeneration and other age-related degenerative diseases, the discovery of actionable molecular targets that can link these perturbations may have therapeutic value.Abbreviation: ATRA: all-trans-retinoic acid; BrdU: bromodeoxyuridine; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; CDKN2A/p16-INK4A: cyclin dependent kinase inhibitor 2A; CMA: chaperone-mediated autophagy; DHI: disc height index; ER: endoplasmic reticulum; IP: immunoprecipitation; IP3: inositol 1,4,5-trisphosphate; ITPR/IP3R: inositol 1,4,5-trisphosphate receptor; IVD: intervertebral disc; IVDD: intervertebral disc degeneration; KD: knockdown; KO: knockout; Leu: leupeptin; MRI: magnetic resonance imaging; MS: mass spectrometry; N/L: NH4Cl and leupeptin; NP: nucleus pulposus; NPC: nucleus pulposus cells; PI: protease inhibitors; PLC: phospholipase C; PLCG1: phospholipase C gamma 1; ROS: reactive oxygen species; RT-qPCR: real-time quantitative reverse transcription PCR; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SASP: senescence-associated secretory phenotype; STV: starvation; TMT: tandem mass tag; TNF: tumor necrosis factor; TP53: tumor protein p53; UPS: ubiquitin-proteasome system.

Changes in mitochondria have been implicated in atrial fibrillation (AF), but their manifestations and significance are poorly understood. Here, we studied changes in mitochondrial morphology and function during AF and assessed the effect of a mitochondrial-targeted intervention in a large animal model.

Atrial cardiomyocytes (ACMs) were isolated from dogs in electrically-driven AF for periods of 24 hours to 3 weeks and from humans with/without longstanding persistent AF. Mitochondrial Ca 2+ -concentration ([Ca 2+ ] Mito ), reactive oxygen species (mtROS) production, membrane potential (ΔΨ m ), permeability transition-pore (mPTP) opening and flavin adenine dinucleotide (FAD) were measured via confocal microscopy; nicotine adenine dinucleotide (NADH) under ultraviolet light. mtROS-production increased within 24 hours and superoxide-dismutase type-2 was significantly reduced from 3-day AF. [Ca 2+ ] Mito and mPTP-opening frequency/duration increased progressively during AF. Mitochondrial depolarization was detectable 24 hours after AF-onset. NADH increased by 15% at 24-hour AF, concomitant with increased pyruvate-dehydrogenase expression, then gradually decreased. Mitochondria enlarged and elongated at 24-hour and 3-day AF, followed by progressive fragmentation, rupture and shrinkage. Mitochondrial fusion protein-1 (MFN1) was reduced from 3-day to 3-week AF and phosphorylated dynamin-related protein-1 (p-DRP1ser-616) increased after 1 week of canine AF and in human AF. Addition of the mitochondrial antioxidant MitoTempo attenuated action-potential shortening and L-type Ca 2+ -current (I CaL )-downregulation in canine and human AF ACMs in vitro . Administration of the orally-active mitochondrial-targeted ubiquinone mitoquinone to dogs during 3-week AF prevented mitochondrial Ca 2+ -overload, mtROS-overproduction, structural damage and abnormalities in ΔΨ m and respiration. Functionally, mitoquinone reduced AF-induced Ca 2+ -current downregulation, action-potential abbreviation, contractile dysfunction and fibrosis, preventing AF-substrate development and AF-sustainability.

Mitochondria show a series of changes during AF, with early hyperfunction and enhanced ROS-generation, followed by progressive damage and dysfunction. Mitochondrial-targeted therapy prevents mitochondrial dysfunction and attenuates adverse AF-related remodeling, positioning mitochondrial protection as a potential novel therapeutic target in AF.

This open question research article highlights mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), which have emerged as crucial cellular structures that challenge our traditional understanding of organelle function. This review highlights the critical importance of MAMs as a frontier in cell biology with far-reaching implications for health, disease and ageing. MAMs serve as dynamic communication hubs between the ER and mitochondria, orchestrating essential processes such as calcium signalling, lipid metabolism and cellular stress responses. Recent research has implicated MAM dysfunction in a wide array of conditions, including neurodegenerative diseases, metabolic disorders, cardiovascular diseases and cancer. The significant lack of biological knowledge behind MAM function emphasizes the need to study these enigmatic subcellular sites in greater detail. Key open questions include the mechanisms controlling MAM formation and disassembly, the full complement of MAM-associated proteins and how MAMs contribute to cellular decision-making and ageing processes. Advancing our understanding of MAMs through interdisciplinary approaches and cutting-edge technologies promises to reveal new insights into fundamental cellular signalling pathways and potentially lead to innovative therapeutic strategies for a range of diseases. As such, MAM research represents a critical open question in biology with the potential to transform our understanding of cellular life and human health.

Diabetic cardiomyopathy (DCM) represents a significant health burden, exacerbated by the global increase in type 2 diabetes mellitus (T2DM). This condition contributes substantially to the morbidity and mortality associated with diabetes, primarily through myocardial dysfunction independent of coronary artery disease. Current treatment strategies focus on managing symptoms rather than targeting the underlying pathophysiological mechanisms, highlighting a critical need for specific therapeutic interventions. This review explores the multifaceted role of empagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, in addressing the complex etiology of DCM. We discuss the key mechanisms by which hyperglycemia contributes to cardiac dysfunction, including oxidative stress, mitochondrial impairment, and inflammation, and how empagliflozin mitigates these effects. Empagliflozin's effects on reducing hospitalization for heart failure and potentially lowering cardiovascular mortality mark it as a promising candidate for DCM management. By elucidating the underlying mechanisms through which empagliflozin operates, this review underscores its therapeutic potential and paves the way for future research into its broader applications in diabetic cardiac care. This synthesis aims to foster a deeper understanding of DCM and encourage the integration of empagliflozin into treatment paradigms, offering hope for improved outcomes in patients suffering from this debilitating condition.

Near-infrared (NIR) persistent luminescence nanoparticles (PLNPs) have significant potential in diagnostic and therapeutic applications owing to their unique persistent luminescence (PersL). However, obtaining high-performance NIR PLNPs remains challenging because of the limitations of current synthesis methods. Herein, we introduce a spatial confinement growth strategy for synthesizing high-performance NIR PLNPs using hollow mesoporous silica (hmSiO2). By calcining precursor ions in the hollow cavity, the yolk size of NIR PLNPs was regulated, yielding well-dispersed Zn1.3Ga1.4Sn0.3O4: Cr0.005, Y0.003@hmSiO2 (ZS) with a yolk-shell structure. Compared to the conventional template method, ZS synthesized via the spatial confinement growth strategy exhibited a 7.7-fold increase in PersL intensity and a threefold increase in specific surface area. As a proof of concept, ZS@PpIX@CaP-AMD (ZPSC-AMD) nanoparticles, with potential for sonodynamic therapy (SDT), were synthesized by loading the sonosensitizer protoporphyrin IX (PpIX) into ZS, coating it with a calcium phosphate (CaP) shell, and modifying it with a tumor-targeting molecule plerixafor (AMD-3100). The tumor enrichment behavior of ZPSC-AMD was monitored by sensitive NIR PersL to guide SDT. Simultaneously, ZPSC-AMD enabled the precise monitoring of tumor accumulation, thereby guiding effective SDT. In addition, Ca2+ released from CaP degradation increased the level of reactive oxygen species during SDT, promoting tumor cell apoptosis. This study outlines a reliable design and synthesis approach for high-performance NIR PLNPs and promotes their development in biomedical applications. STATEMENT OF SIGNIFICANCE: The potential of near infrared (NIR) persistent luminescence nanoparticles (PLNPs) in bio applications is hindered by limitations in the synthesis method. In this article, we proposed a spatial confinement growth strategy of high-performance NIR PLNPs. The obtained PLNPs with yolk-shell structure showed a 7.7-fold increase in PersL intensity and a threefold increase in specific surface area, compared with the commonly used template method. Due to the advantages, sonodynamic therapeutic nanoparticles were constructed based on the above PLNPs, where persistent luminescence was used for ultrasensitive imaging to determine the optimal timing in sonodynamic therapy. In addition, the multifunctional calcium phosphate shell elevated the intracellular reactive oxygen species level to promote tumor cell apoptosis.

β-asarone, an effective volatile oil component of Acorus chinensis, has been found to hold beneficial effects on Parkinson's disease (PD), but its mechanism remains incompletely understood. Drosophila melanogaster with PTEN induced kinase 1 (PINK1) mutations, a prototype PD model, was used in this study. We found that calcium chelation profoundly alleviated a spectrum of PD symptoms. Whereas, calcium supplementation made the case worse, suggesting accumulated calcium contributes to progression of PD. β-asarone administration decreased Ca2+ level in PD flies, accompanied by alleviated behavioral and neural defects. Further study demonstrated that β-asarone downregulated L-type Ca2+ channels (Dmca1D), which was increased in PD flies. Besides, β-asarone decreased expression of 1,4,5 - trisphosphate receptor (Itpr), which is responsible for calcium release from endoplasmic reticulum (ER). Knockdown of either Dmca1D or Itpr specifically in dopaminergic neurons alleviated behavioral and neural defects in PD flies. While overexpression of Itpr aggravated PD symptoms. The results indicated that increased intracellular calcium influx and release triggers dysregulation of calcium homeostasis in PD flies. And β-asarone prevents PD by restoring Ca2+ homeostasis. Overall, the study demonstrated that β-asarone can serve as a new prospective medication against PD or other diseases associated with dysregulation of Ca2+ homeostasis.

Oxidative stress in endothelial cells is pivotal in diabetic retinopathy (DR), with mitochondrial homeostasis being crucial to mitigate this stress. This study explored the roles of mitochondrial sirtuins (SIRTs) in high glucose (HG)-induced oxidative stress, related endothelial impairment, and mitochondrial homeostasis damage in rat retinal microvascular endothelial cells (RMECs). RMECs were cultured under HG or equivalent osmotic conditions. Cell viability was assessed using the Cell Counting Kit-8 assay, whereas cell death and survival were determined via calcein-AM/propidium iodide double staining. Reactive oxygen species (ROS) levels were measured using 2',7'-dichlorofluorescein fluorescence. Expression of mitochondrial SIRTs3-5 and key mitochondrial homeostasis molecules was quantified by the quantitative real-time polymerase chain reaction and confirmed by western blotting. Mitochondrial morphology was evaluated using electron microscopy and the MitoTracker fluorescent probe. A SIRT3-overexpressing RMEC line was constructed to assess the role of SIRT3 in oxidative stress and mitochondrial dynamics. After 48 h of HG exposure, cell viability was significantly reduced, with a concomitant increase in cell death and ROS levels, alongside a marked decrease in SIRT3 expression and molecules associated with mitochondrial dynamics. SIRT3 overexpression reversed these effects, particularly increasing the mitochondrial fusion-related molecule, optic atrophy 1 (OPA1). However, the OPA1 inhibitor, MYLS22, blocked the protective effect of SIRT3, leading to more dead cells, a higher ROS level, and intensified mitochondrial fragmentation. These results suggest that SIRT3 is involved in HG-induced imbalanced mitochondrial dynamics of endothelial cells in DR, potentially through the OPA1 pathway.

Acute wounds result from damage to the skin barrier, exposing underlying tissues and increasing susceptibility to bacterial and other pathogen infections. Improper wound care increases the risk of exposure and infection, often leading to chronic nonhealing wounds, which cause significant patient suffering. Early wound repair can effectively prevent the development of chronic nonhealing wounds. In this study, Ca-Gallic Acid (CaGA) nanozymes with multienzyme catalytic activity were constructed for treating acute wounds by coordinating Ca ions with gallic acid. CaGA nanozymes exhibit high superoxide dismutase/catalase (SOD/CAT) catalytic activity and good antioxidant performance in vitro. In vitro experiments demonstrated that CaGA nanozymes can effectively promote cell migration, efficiently scavenge ROS, maintain mitochondrial homeostasis, reduce inflammation, and decrease cell apoptosis. In vivo, CaGA nanozymes promoted granulation tissue formation, accelerated collagen fiber deposition, and reconstructed skin appendages, thereby accelerating acute wound healing. CaGA nanozymes have potential clinical application value in wound healing treatment.

Mitochondria are essential for cellular function and viability, serving as central hubs of metabolism and signaling. They possess various metabolic and quality control mechanisms crucial for maintaining normal cellular activities. Mitochondrial genetic disorders can arise from a wide range of mutations in either mitochondrial or nuclear DNA, which encode mitochondrial proteins or other contents. These genetic defects can lead to a breakdown of mitochondrial function and metabolism, such as the collapse of oxidative phosphorylation, one of the mitochondria's most critical functions. Mitochondrial diseases, a common group of genetic disorders, are characterized by significant phenotypic and genetic heterogeneity. Clinical symptoms can manifest in various systems and organs throughout the body, with differing degrees and forms of severity. The complexity of the relationship between mitochondria and mitochondrial diseases results in an inadequate understanding of the genotype-phenotype correlation of these diseases, historically making diagnosis and treatment challenging and often leading to unsatisfactory clinical outcomes. However, recent advancements in research and technology have significantly improved our understanding and management of these conditions. Clinical translations of mitochondria-related therapies are actively progressing. This review focuses on the physiological mechanisms of mitochondria, the pathogenesis of mitochondrial diseases, and potential diagnostic and therapeutic applications. Additionally, this review discusses future perspectives on mitochondrial genetic diseases.

Hypertension is a leading risk factor for stroke, heart disease and chronic kidney disease. Multiple interacting factors and organ systems increase blood pressure and cause target-organ damage. Among the many molecular elements involved in the development of hypertension are reactive oxygen species (ROS), which influence cellular processes in systems that contribute to blood pressure elevation (such as the cardiovascular, renal, immune and central nervous systems, or the renin-angiotensin-aldosterone system). Dysregulated ROS production (oxidative stress) is a hallmark of hypertension in humans and experimental models. Of the many ROS-generating enzymes, NADPH oxidases are the most important in the development of hypertension. At the cellular level, ROS influence signalling pathways that define cell fate and function. Oxidative stress promotes aberrant redox signalling and cell injury, causing endothelial dysfunction, vascular damage, cardiovascular remodelling, inflammation and renal injury, which are all important in both the causes and consequences of hypertension. ROS scavengers reduce blood pressure in almost all experimental models of hypertension; however, clinical trials of antioxidants have yielded mixed results. In this Review, we highlight the latest advances in the understanding of the role and the clinical implications of ROS in hypertension. We focus on cellular sources of ROS, molecular mechanisms of oxidative stress and alterations in redox signalling in organ systems, and their contributions to hypertension.

Atherosclerosis is a progressive inflammatory disease within the large and medium arteries. SUCNR1(Succinate receptor 1) has been reported to regulate the inflammatory response in cardiovascular diseases, but how it works in atherosclerosis remains unclear. In this study, we observed that SUCNR1 is upregulated in endothelial cells within human atherosclerotic lesions. The deletion of SUCNR1 in vascular endothelial cells can mitigate the progression of atherosclerotic lesions in high-fat diet ApoE-/- mice. The overexpression or activation of SUCNR1 intensified endoplasmic reticulum stress and mitochondria-endoplasmic reticulum interactions. Moreover, SUCNR1 exacerbated mitochondrial injury, mtDNA leakage, and the activation of cGAS-STING signaling. Elevated mitochondrial damage, ER-mitochondrial interactions, and inflammation induced by SUCNR1 activation were blocked by the endoplasmic reticulum stress inhibitor. Collectively, these findings suggest that SUCNR1 promotes atherosclerosis through endoplasmic reticulum stress signaling mediated ER-mitochondrial crosstalk and its downstream cGAS-STING pathway. Our results provide new insights into the mechanism of SUCNR1 in atherosclerosis and inhibiting endoplasmic reticulum stress signaling may provide a promising strategy to prevent and treat atherosclerosis.

Drugs that eliminate senescent cells, senolytics, can be powerful when combined with prosenescence cancer therapies. Using a CRISPR/Cas9-based genetic screen, we identify here SLC25A23 as a vulnerability of senescent cancer cells. Suppressing SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation, and interferes with redox signaling, leading to death of senescent cells. These effects can be replicated by salinomycin, a cation ionophore antibiotic. Salinomycin prompts a pyroptosis-apoptosis-necroptosis (PAN)optosis-like cell death in senescent cells, including apoptosis and two forms of immunogenic cell death: necroptosis and pyroptosis. Notably, we observed that salinomycin treatment or SLC25A23 suppression elevates reactive oxygen species, upregulating death receptor 5 via Jun N-terminal protein kinase (JNK) pathway activation. We show that a combination of a death receptor 5 (DR5) agonistic antibody and salinomycin is a robust senolytic cocktail. We provide evidence that this drug combination provokes a potent natural killer (NK) and CD8+ T cell-mediated immune destruction of senescent cancer cells, mediated by the pyroptotic cytokine interleukin 18 (IL18).