Mitochondrial Oxidative Stress Research Articles

Mitochondria-targeting Cu2-xSe-TPP with dual enzyme activity alleviates Alzheimer's disease by modulating oxidative stress

Mitochondrial dysfunction in microglia has been implicated as a key pathogenesis of most neurodegenerative diseases including Alzheimer's disease (AD). Abnormal production of reactive oxygen species (ROS) and neuroinflammation caused by mitochondrial oxidative stress are important factors leading to neuronal death in AD. Herein, a "dual brake" strategy to synergistically halt mitochondrial dysfunction and neuroinflammation targeting mitochondria in microglia is proposed. To achieve this goal, (3-carboxypropyl) triphenyl-phosphonium bromide (TPP)-modified Cu2-xSe nanozymes (Cu2-xSe-TPP NPs) with dual enzyme-like activities was designed. Cu2-xSe-TPP NPs with superoxide dismutase-mimetic (SOD) and catalase-mimetic (CAT) activities can effectively scavenge ROS in the mitochondria of microglia and relieve mitochondrial oxidative stress. In vivo studies demonstrated that Cu2-xSe-TPP NPs can alleviate oxidative stress and promote neuroprotection in the hippocampus of AD model mice. In addition, Cu2-xSe-TPP NPs can regulate the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, promote Aβ phagocytosis and reshape the AD inflammatory microenvironment, thus effectively attenuating AD neuropathology and rescuing cognitive deficits in AD model mice. Taken together, this strategy preventing mitochondrial damage and remodeling the inflammatory microenvironment will provide a new perspective for AD therapy.

Lutein and zeaxanthin reduce neuronal cell damage caused by lipid peroxidation

Oxidative stress and lipid peroxide levels in the brain increase with aging. The carotenoids lutein and zeaxanthin have potent antioxidant properties and the ability to improve cognitive function. However, their effects on neuronal damage via lipid peroxidation remain unknown. Therefore, we aimed to elucidate the effects of these carotenoids on neuronal damage induced by accumulated peroxidized lipids. We developed an oxidative stress model of lipid peroxidation-induced neuronal damage using differentiated neuronal cells derived from human neuroblastoma SH-SY5Y cells in vitro. Combining rotenone and RSL3 increased mitochondrial oxidative stress and lipid reactive oxygen species (ROS), which resulted in enhanced neuronal damage. Lutein and zeaxanthin were added to the cells for 1 week, and these carotenoids suppressed mitochondrial oxidative stress and lipid peroxidation in differentiated neuronal cells and mitigated neuronal damage. Further investigation is required to clarify the underlying pathways in detail.

Foodborne iron overload induces oxidative stress and causes mitochondrial damage in the liver of grass carp (Ctenopharyngodon idellus)

Iron is essential to biological processes such as energy metabolism and oxygen transport. However, excessive iron can cause iron overload and ultimately result in tissue damage. To date, the damage mechanism of foodborne iron overload in aquatic animals is still unclear. This study used grass carp (Ctenopharyngodon idellas) as the research subject to establish a chronic iron overload model by feeding diets with different iron levels, and combined in vitro experiments to investigate the mechanisms of iron overload-induced damage. The growth performance and liver HE staining indicated that a high‑iron diet led to decreased growth in grass carp, accompanied by hepatic iron deposition. ELISA and qRT-PCR analysis data revealed that a high‑iron diet disrupted the antioxidant balance and modulated the expression of genes associated with iron metabolism. CCK-8 determination results revealed that treatment of L8824 cells with ferri ammonii citras (FAC) resulted in iron overload, led to disruption of iron metabolism and enhanced the intracellular production of reactive oxygen species (ROS), and caused lipid peroxidation. Furthermore, qRT-PCR analysis results showed that the treatment of L8824 cells with FAC resulted in a significant up-regulation of genes associated with antioxidant, apoptosis, and necrosis pathways, and increased the rate of apoptosis. In addition, fluorescence microscopy observation and mitochondrial DNA detection data showed that excess iron could increase the iron accumulation in mitochondria and the production of mtROS, reduce the mitochondrial membrane potential, and finally cause mitochondria damage. In conclusion, our research offers invaluable insights that iron overload leads to disrupted intracellular iron pool stability, causing mitochondrial damage and oxidative stress, eventually causing cell death.

New Mitochondria-Targeted Fisetin Derivative Compromises Mitophagy and Limits Survival of Drug-Induced Senescent Breast Cancer Cells.

Mitochondria are considered as promising targets for cancer treatment. In the present study, triphenyl phosphonium cationic group-conjugated fisetin (mito-fisetin) was synthesized, and its anticancer activity was investigated in several cellular models of estrogen receptor (ER)-positive breast cancer in vitro and in vivo in proliferating and tamoxifen-promoted senescent states. Mito-fisetin, when used at low micromolar concentrations, stimulated the dissipation of mitochondrial membrane potential and oxidative stress, and affected mitochondrial function, resulting in apoptosis induction in senescent breast cancer cells. Mito-fisetin-mediated cytotoxicity was due to increased levels of phosphorylated AMPK, decreased levels of AKT and HSP90, and impaired mitophagic response, as judged by the analysis of the markers of mitophagosome formation. Senescent breast cancer cells were found to be more sensitive to mito-fisetin treatment than proliferating ones. We postulate that mitochondrial targeting in the case of fisetin may be considered as a promising anticancer and senotherapeutic strategy to eliminate drug-resistant senescent breast cancer cells.

Single-cell multi-omics map of human fetal blood in Down syndrome

Down syndrome predisposes individuals to haematological abnormalities, such as increased number of erythrocytes and leukaemia in a process that is initiated before birth and is not entirely understood1–3. Here, to understand dysregulated haematopoiesis in Down syndrome, we integrated single-cell transcriptomics of over 1.1 million cells with chromatin accessibility and spatial transcriptomics datasets using human fetal liver and bone marrow samples from 3 fetuses with disomy and 15 fetuses with trisomy. We found that differences in gene expression in Down syndrome were dependent on both cell type and environment. Furthermore, we found multiple lines of evidence that haematopoietic stem cells (HSCs) in Down syndrome are ‘primed’ to differentiate. We subsequently established a Down syndrome-specific map linking non-coding elements to genes in disomic and trisomic HSCs using 10X multiome data. By integrating this map with genetic variants associated with blood cell counts, we discovered that trisomy restructured regulatory interactions to dysregulate enhancer activity and gene expression critical to erythroid lineage differentiation. Furthermore, as mutations in Down syndrome display a signature of oxidative stress4,5, we validated both increased mitochondrial mass and oxidative stress in Down syndrome, and observed that these mutations preferentially fell into regulatory regions of expressed genes in HSCs. Together, our single-cell, multi-omic resource provides a high-resolution molecular map of fetal haematopoiesis in Down syndrome and indicates significant regulatory restructuring giving rise to co-occurring haematological conditions.

Inducible and reversible SOD2 knockdown in mouse skeletal muscle drives impaired pyruvate oxidation and reduced metabolic flexibility.

Skeletal muscle mitochondrial dysfunction is a key characteristic of aging muscle and contributes to age related diseases such as sarcopenia, frailty, and type 2 diabetes. Mitochondrial oxidative distress has been implicated as a driving factor in these age-related diseases, however whether it is a cause, or a consequence of mitochondrial dysfunction remains to be determined. The development of more flexible genetic models is an important tool to test the mechanistic role of mitochondrial oxidative stress on skeletal muscle metabolic dysfunction. We characterize a new model of inducible and reversible mitochondrial redox stress using a tetracycline controlled skeletal muscle specific short hairpin RNA targeted to superoxide dismutase 2 (iSOD2). iSOD2 KD and control (CON) animals were administered doxycycline for 3- or 12- weeks and followed for up to 24 weeks and mitochondrial respiration and muscle contraction were measured to define the time course of SOD2 KD and muscle functional changes and recovery. Maximum knockdown of SOD2 protein occurred by 6 weeks and recovered by 24 weeks after DOX treatment. Mitochondrial aconitase activity and maximum mitochondrial respiration declined in KD muscle by 12 weeks and recovered by 24 weeks. There were minimal changes in gene expression between KD and CON muscle. Twelve-week KD showed a small, but significant decrease in muscle fatigue resistance. The primary phenotype was reduced metabolic flexibility characterized by impaired pyruvate driven respiration when other substrates are present. The pyruvate dehydrogenase kinase inhibitor dichloroacetate partially restored pyruvate driven respiration, while the thiol reductant DTT did not. We use a model of inducible and reversible skeletal muscle SOD2 knockdown to demonstrate that elevated matrix superoxide reversibly impairs mitochondrial substrate flexibility characterized by impaired pyruvate oxidation. Despite the bioenergetic effect, the limited change in gene expression suggests that the elevated redox stress in this model is confined to the mitochondrial matrix.

Lithocarpus polystachyus Rehd. ameliorates cerebral ischemia/reperfusion injury through inhibiting PI3K/AKT/NF-κB pathway and regulating NLRP3-mediated pyroptosis.

Ischemic stroke (IS) is a serious threat to human life and health, and cerebral ischemia/reperfusion injury (CIRI) exacerbates IS by enhancing neuroinflammation and oxidative stress. Sweet tea (ST) comprises several bioactive components, such as phlorizin, trilobatin, and phloretin, with diverse pharmacological activities. However, it remains uncertain whether ST can confer protection against CIRI. In this study, we aimed to investigate the impact and potential underlying mechanism of ST in the context of CIRI. CIRI model were established in male sprague dawley (SD) rats. The neurobehavioral assessment, the volume of cerebral infarction and the morphology of neurons were measured to complete the preliminary pharmacodynamic study. The therapeutic targets and pathways of ST on IS were obtained by protein-protein interaction, molecular docking and Metascape database. The predicted results were further verified in vivo. Our results revealed that ST treatment significantly ameliorated brain damage in rats subjected to CIRI by mitigating mitochondrial oxidative stress and neuroinflammation. Additionally, we identified the PI3K/AKT/NF-κB pathway and the NLRP3-mediated pyroptosis axis as crucial processes, with molecular docking suggested direct interactions between the main compounds of ST and NLRP3. ST safeguards against CIRI-induced neuronal loss, neuroinflammation and oxidative stress through the inhibition of the PI3K/AKT/NF-κB pathway and the regulation of NLRP3-mediated pyroptosis.

Mitochondrial membrane potential and oxidative stress interact to regulate Oma1-dependent processing of Opa1 and mitochondrial dynamics.

Mitochondrial form and function are regulated by the opposing forces of mitochondrial dynamics: fission and fusion. Mitochondrial dynamics are highly active and consequential during neuronal ischemia/reperfusion (I/R) injury. Mitochondrial fusion is executed at the mitochondrial inner membrane by Opa1. The balance of long (L-Opa1) and proteolytically cleaved short (S-Opa1) isoforms is critical for efficient fusion. Oma1 is the predominant stress-responsive protease for Opa1 processing. In neuronal cell models, we assessed Oma1 and Opa1 regulation during mitochondrial stress. In an immortalized mouse hippocampal neuron line (HT22), Oma1 was sensitive to mitochondrial membrane potential depolarization (rotenone, FCCP) and hyperpolarization (oligomycin). Further, oxidative stress was sufficient to increase Oma1 activity and necessary for depolarization-induced proteolysis. We generated Oma1 knockout (KO) HT22 cells that displayed normal mitochondrial morphology and fusion capabilities. FCCP-induced mitochondrial fragmentation was exacerbated in Oma1 KO cells. However, Oma1 KO cells were better equipped to perform restorative fusion after fragmentation, presumably due to preserved L-Opa1. We extended our investigations to a combinatorial stress of neuronal oxygen-glucose deprivation and reoxygenation (OGD/R), where we found that Opa1 processing and Oma1 activation were initiated during OGD in an ROS-dependent manner. These findings highlight a novel dependence of Oma1 on oxidative stress in response to depolarization. Further, we demonstrate contrasting fission/fusion roles for Oma1 in the acute response and recovery stages of mitochondrial stress. Collectively, our results add intersectionality and nuance to the previously proposed models of Oma1 activity.

6-Gingerol improves lipid metabolism disorders in skeletal muscle by regulating AdipoR1/AMPK signaling pathway

BackgroundTo delve into the precise mechanisms by which 6-gingerol ameliorates lipid metabolism disorders in skeletal muscle. MethodsThe level of triglycerides (TG) was used to evaluate lipid deposition. In skeletal muscle, transmission electron microscopy (TEM) was employed to observe mitochondrial morphology. Additionally, PCR was applied to detect mitochondrial biogenesis, and levels of malondialdehyde (MDA), catalase (CAT), glutathione, r-glutamyl cysteingl+glycine (GSH) and nicotinamide adenine dinucleotide (NADH) were measured to assess mitochondrial oxidative stress levels. In vivo, flow cytometry and immunofluorescence assays were conducted to quantify reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). Furthermore, the Seahorse XF assays was utilized to assess mitochondrial respiratory capacity. Fluorescence confocal microscopy and molecular docking were applied to analyze the binding of 6-gingerol and adiponectin receptor 1 (AdipoR1). The expression of AdipoR1, AMPK, PGC-1α and SIRT1 were detected by Western Blot. ResultsIn vivo, 6-gingerol could reduce body weight in mice induced by a high-fat diet, enhance metabolic profiles in plasma, decrease lipid accumulation in skeletal muscle and liver, and elevate adiponectin levels. In skeletal muscle, it could restore mitochondrial morphology, boost mitochondrial copy number and biogenesis, and mitigate oxidative stress. In vitro, 6-gingerol may directly interact with AdipoR1 to upregulate the expression of downstream proteins p-AMPK, SIRT1, and PGC-1α, leading to a reduction in lipid deposition, a decrease in ROS production, an increase in mitochondrial membrane potential, and an enhancement of mitochondrial respiratory capacity in C2C12 myotubes. Conclusion6-Gingerol ameliorated lipid metabolism in skeletal muscle by regulating the AdipoR1/AMPK signaling pathway.

Melatonin alleviates high glucose-induced cardiomyocyte injury through suppressing mitochondrial FUNDC1-DRP1 axis.

To use H9c2 cardiomyocytes to establish a diabetic cardiomyopathic model by exposing these cells to high glucose (HG), followed by treating them with melatonin (MEL) or plasmid vectors overexpressing FUN14 Domain Containing 1 (FUNDC1). We employed quantitative real-time PCR, mitochondrial staining, and biochemical assays to measure the activity of various antioxidant and mitochondrial complex functions under various treatment conditions. Our results showed that HG induced the expression of FUNDC1 and increased mitochondrial oxidative stress and fragmentation, while MEL treatment reversed most of these pathological effects. Moreover, HG exposure activated dynamin-related protein 1 expression and its translocation to mitochondria. Modulation of AMP-activated protein kinase level was found to be another pathological hallmark. In silico molecular docking, analysis revealed that MEL could directly bind the catalytic groove of FUNDC1 through Van der Waal's force and hydrogen bonding. Finally, MEL ameliorated diabetic cardiomyopathy-induced mitochondrial injury through FUNDC1 in vivo. Hyperglycemia induced mitochondrial fragmentation and altered electron transport chain complex functions, which could be ameliorated by MEL treatment, suggesting its potential as a cardiovascular therapeutic.

Hederagenin inhibits mitochondrial damage in Parkinson’s disease via mitophagy induction

BackgroundParkinson's disease (PD) is a neurodegenerative disorder marked by the loss of dopaminergic neurons and the formation of α-synuclein aggregates. Mitochondrial dysfunction and oxidative stress are pivotal in PD pathogenesis, with impaired mitophagy contributing to the accumulation of mitochondrial damage. Hederagenin (Hed), a natural triterpenoid, has shown potential neuroprotective effects; however, its mechanisms of action in PD models are not fully understood. MethodWe investigated the effects of Hed on 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in SH-SY5Y cells by assessing cell viability, mitochondrial function, and oxidative stress markers. Mitophagy induction was evaluated using autophagy and mitophagy inhibitors and fluorescent staining techniques. Additionally, transgenic Caenorhabditis elegans (C. elegans) models of PD were used to validate the neuroprotective effects of Hed in vivo by focusing on α-synuclein aggregation, mobility, and dopaminergic neuron integrity. ResultsHed significantly enhanced cell viability in 6-OHDA-treated SH-SY5Y cells by inhibiting cell death and reducing oxidative stress. It ameliorated mitochondrial damage, evidenced by decreased mitochondrial superoxide production, restored membrane potential, and improved mitochondrial morphology. Hed also induced mitophagy, as shown by increased autophagosome formation and reduced oxidative stress; these effects were diminished by autophagy and mitophagy inhibitors. In C. elegans models, Hed activated mitophagy and reduced α-synuclein aggregation, improved mobility, and mitigated the loss of dopaminergic neurons. RNA interference targeting the mitophagy-related genes pdr-1 and pink-1 partially reversed these benefits, underscoring the role of mitophagy in Hed's neuroprotective actions. ConclusionHed exhibits significant neuroprotective effects in both in vitro and in vivo PD models by enhancing mitophagy, reducing oxidative stress, and mitigating mitochondrial dysfunction. These findings suggest that Hed holds promise as a therapeutic agent for PD, offering new avenues for future research and potential drug development.

Di-(2-ethylhexyl) phthalate induces prepubertal testicular injury through MAM-related mitochondrial calcium overload in Leydig and Sertoli cell apoptosis

As one of the most prevalent environmental endocrine disruptors, di-(2-ethylhexyl) phthalate (DEHP) is known for its significant developmental toxicity to the male reproductive system in humans and mice. Prepubertal exposure to DEHP has been shown to cause testicular damage, but the underlying mechanisms require further investigation. To investigate this effect, prepubertal mice were exposed to 100, 250 or 500 mg/kg body weight (bw) of DEHP for 14 days, which resulted in impaired histological structure and increased apoptosis of the testes. RNA sequencing (RNA-seq) of testicular tissue suggested that DEHP led to injury in Leydig and Sertoli cells. To further elucidate these mechanisms, we conducted experiments using immature mouse Leydig (TM3) and Sertoli (TM4) cells, and exposed them to 200 μM mono-(2-ethylhexyl) phthalate (MEHP), the primary metabolite of DEHP, for 24 h. We found that MEHP exposure induced oxidative stress injury and promoted cell apoptosis, and that cotreatment with N-acetylcysteine partially reversed these injuries. Given the close association between oxidative stress and mitochondrial calcium levels, we demonstrated that MEHP exposure disrupted mitochondria and increased mitochondrial calcium levels. In addition, MEHP exposure facilitated the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs), upregulated protein expression and enhanced the interactions of the IP3R3-Grp75-VDAC1 complex. Furthermore, inhibition of calcium transfer in the IP3R3-Grp75-VDAC1-MCU axis relieved MEHP-induced mitochondrial injury, oxidative stress and apoptosis in TM3 and TM4 cells. This study highlights the importance of MAM-mediated mitochondrial calcium overload and the subsequent apoptosis of Leydig and Sertoli cells as pivotal factors contributing to testicular injury induced by prepubertal exposure to DEHP.

Antiallodynic and antihyperalgesic effects of decursin associated with correcting mitochondrial dysfunction and oxidative stress in type 1 diabetic mice

A substantial proportion of diabetic patients suffer a debilitating and persistent pain state, known as peripheral painful neuropathy that necessitates improved therapy or antidote. Decursin, a major active ingredient from Angelica gigas Nakai, has been reported to possess antidepressant activity in preclinical studies. As antidepressants have been typically used as standard agents against persistent neuropathic pain, this study aimed to probe the effect of decursin on neuropathic pain associated with streptozotocin-induced type 1 diabetes in male C57BL6J mice. The Hargreaves test and the von Frey test were used to assess pain-like behaviors, shown as heat hyperalgesia and mechanical allodynia respectively. Chronic treatment of diabetic mice with decursin not only ameliorated the established symptoms of heat hyperalgesia and mechanical allodynia, but also arrested the development of these pain states given preemptively at low doses. Although decursin treatment hardly impacted on metabolic disturbance in diabetic mice, it ameliorated exacerbated oxidative stress in pain-associated tissues, improved mitochondrial bioenergetics in dorsal root ganglion neurons, and restored nerve conduction velocity and blood flow in sciatic nerves. Notably, the analgesic actions of decursin were modified by pharmacologically manipulating redox status and mitochondrial bioenergetics. These findings unveil the analgesic activity of decursin, an effect that is causally associated with its bioenergetics-enhancing and antioxidant effects, in mice with type 1 diabetes.

Is SIRT3 and Mitochondria a Reliable Target for Parkinson's Disease and Aging? A Narrative Review.

Aging is a complicated degenerative process that has been thoroughly researched in a variety of taxa, including mammals, worms, yeast, and flies. One important controller of organismal lifetime is the conserved deacetylase protein known as silencing information regulator 2 (SIR2). It has been demonstrated that overexpressing SIR2 lengthens the life span in worms, flies, and yeast, demonstrating its function in enhancing longevity. SIRT3 is a member of the sirtuin protein family, identified as a major regulator of longevity and aging. Sirtuin 3 (SIRT3), a possible mitochondrial tumor suppressor, has been explicitly linked to the control of cellular reactive oxygen species (ROS) levels, the Warburg effect, and carcinogenesis. SIRT3 plays a significant part in neurodegenerative illnesses such as Parkinson's and Alzheimer's disease by decreasing the oxidative stress in mitochondria and reducing the ROS levels. Furthermore, SIRT3 has been linked to metabolic and cardiovascular disorders, indicating its wider role in the pathophysiology of disease and possible therapeutic applications.

Dysfunctional cardiac energy transduction, mitochondrial oxidative stress, oncogenic and apoptotic signaling in DiNP-induced asthma in murine model.

Diisononyl phthalate (DiNP) has been associated with the development of allergies, asthma, and allergic airway inflammation. Through a complex interplay of signals and feedback mechanisms, the lungs communicate with the heart to ensure maintenance of homeostasis and supporting the body's metabolic demands. In the current study, we assessed the crosstalk between DiNP-induced asthma and cardiac cellular respiration, oxidative stress, apoptotic potential, and induction of oncogenic factors. Ten male BALB/c mice with a weight range of 20-30g were divided into two groups, each comprising five mice. Group 1 (control), was administered saline orally for a duration of 30days. In contrast, group 2 (DiNP group), received 50mg/kg of DiNP to induce asthma. After the final administration and asthma induction, the mice were euthanized, and their hearts were excised, processed, and subjected to biochemical analyses. The DiNP group had downregulated (P < 0.05) activities of the enzymes of glycolysis, tricyclic acid cycle, and electron transport chain except the hexokinase and succinate dehydrogenase activity which were upregulate relative to control. Also, oxidative distress markers (GSH, CAT, and MDA and SOD) were also perturbed. Biomarkers of inflammation (MPO and NO) were considerably higher (P < 0.05) in the heart of DiNP-induced asthma mice as compared with the control group. Furthermore, DiNP-induced asthma group has an increased cardiac caspase-3, Bax, c-Myc and K-ras, and p53 while the Bcl2 decreased when compared with control. Overall, the findings indicate that DiNP-induced asthma impairs cardiac functions by induction of key cardiac oncogenes, downregulation of cardiac energy, transduction of enzymes, and promotion of oxidative stress and cellular death.

Glial swip-10 controls systemic mitochondrial function, oxidative stress, and neuronal viability via copper ion homeostasis

Cuprous copper [Cu(I)] is an essential cofactor for enzymes that support many fundamental cellular functions including mitochondrial respiration and suppression of oxidative stress. Neurons are particularly reliant on mitochondrial production of ATP, with many neurodegenerative diseases, including Parkinson's disease, associated with diminished mitochondrial function. The gene MBLAC1 encodes a ribonuclease that targets pre-mRNA of replication-dependent histones, proteins recently found in yeast to reduce Cu(II) to Cu(I), and when mutated disrupt ATP production, elevates oxidative stress, and severely impacts cell growth. Whether this process supports neuronal and/or systemic physiology in higher eukaryotes is unknown. Previously, we identified swip-10, the putative Caenorhabditis elegans ortholog of MBLAC1, establishing a role for glial swip-10 in limiting dopamine (DA) neuron excitability and sustaining DA neuron viability. Here, we provide evidence from computational modeling that SWIP-10 protein structure mirrors that of MBLAC1 and locates a loss of function coding mutation at a site expected to disrupt histone RNA hydrolysis. Moreover, we find through genetic, biochemical, and pharmacological studies that deletion of swip-10 in worms negatively impacts systemic Cu(I) levels, leading to deficits in mitochondrial respiration and ATP production, increased oxidative stress, and neurodegeneration. These phenotypes can be offset in swip-10 mutants by the Cu(I) enhancing molecule elesclomol and through glial expression of wildtype swip-10. Together, these studies reveal a glial-expressed pathway that supports systemic mitochondrial function and neuronal health via regulation of Cu(I) homeostasis, a mechanism that may lend itself to therapeutic strategies to treat devastating neurodegenerative diseases.

The Worsening of Myocardial Ischemia-Reperfusion Injury in Uremic Cardiomyopathy is Further Aggravated by PM2.5 Exposure: Mitochondria Serve as the Central Focus of Pathology.

Uremic cardiomyopathy (UC) represents a complex syndrome characterized by different cardiac complications, including systolic and diastolic dysfunction, left ventricular hypertrophy, and diffuse fibrosis, potentially culminating in myocardial infarction (MI). Revascularization procedures are often necessary for MI management and can induce ischemia reperfusion injury (IR). Despite this clinical relevance, the role of fine particulate matter (PM2.5) in UC pathology and the underlying subcellular mechanisms governing this pathology remains poorly understood. Hence, we investigate the impact of PM2.5 exposure on UC susceptibility to IR injury. Using a rat model of adenine-induced chronic kidney disease (CKD), the animals were exposed to PM2.5 at 250µg/m3 for 3h daily over 21days. Subsequently, hearts were isolated and subjected to 30min of ischemia followed by 60min of reperfusion to induce IR injury. UC hearts exposed to PM2.5 followed by IR induction (Adenine + PM_IR) exhibited significantly impaired cardiac function and increased cardiac injury (increased infarct size and apoptosis). Analysis at the subcellular level revealed reduced mitochondrial copy number, impaired mitochondrial bioenergetics, decreased expression of PGC1-α (a key regulator of mitochondrial biogenesis), and compromised mitochondrial quality control mechanisms. Additionally, increased mitochondrial oxidative stress and perturbation of the PI3K/AKT/AMPK signaling axis were evident. Our findings therefore collectively indicate that UC myocardium when exposed to PM2.5 is more vulnerable to IR-induced injury, primarily due to severe mitochondrial impairment.

The study on the role of O-GlcNAcylation of SIRT3 in regulating mitochondrial oxidative stress during simulate myocardial ischemia-reperfusion.

Myocardial ischemia-reperfusion injury (MIRI) is a significant complication following reperfusion therapy after myocardial infarction. Mitochondrial oxidative stress is a critical factor in MIRI, and Sirtuin 3 (SIRT3), as a major mitochondrial deacetylase, plays a key protective role, with its activity potentially regulated by O-GlcNAcylation. This study used the H9C2 cell line to establish a simulated ischemia/reperfusion (SI/R) model, we utilized co-immunoprecipitated to validate the relationship between O-GlcNAc transferase (OGT) and SIRT3, demonstrated SIRT3 O-GlcNAcylation sites through LC-MS/MS, and performed site mutations using CRISPR/Cas9 technology. The results were validated using immunoblotting. SIRT3 and superoxide dismutase 2 (SOD2) activities were detected using a fluorometric assay, while mitochondrial reactive oxygen species (MROS) levels and cellular apoptosis were assessed using immunofluorescence. We have identified an interaction between SIRT3 and OGT, where SIRT3 undergoes dynamic O-GlcNAcylation at the S190 site, facilitating SIRT3 deacetylase activity. During SI/R, elevated levels of O-GlcNAcylation activate SOD2 by promoting SIRT3 enzyme activity, thereby inhibiting excessive MROS production. This significantly mitigates the occurrence of malignant autophagy in myocardial cells during reperfusion, promoting their survival. Conversely, blocking SIRT3 O-GlcNAcylation at the S190 site exacerbates SI/R injury. We demonstrate that O-GlcNAcylation is a crucial post-translational modification (PTM) of SIRT3 during SI/R, shedding light on a promising mechanism for future therapeutic approaches.

Probiotic Lactobacillus plantarum 299v supplementation in patients with major depression in a double-blind, randomized, placebo-controlled trial: A metabolomics study

BackgroundUnderstanding the multifactorial nature of major depressive disorder (MDD) is crucial for tailoring treatments. However, the complex interplay of various factors underlying the development and progression of MDD poses significant challenges. Our previous study demonstrated improvements in cognitive functions in MDD patients undergoing treatment with selective serotonin reuptake inhibitors (SSRIs) supplemented with Lactobacillus plantarum 299v (LP299v). MethodsTo elucidate the biochemical mechanisms underlying cognitive functions improvements, we explored underlying metabolic changes. We employed multi-platform metabolomics, including LC-QTOF-MS and CE-TOF-MS profiling, alongside chiral LC-QqQ-MS analysis for amino acids. ResultsSupplementation of SSRI treatment with LP299v intensified the reduction of long-chain acylcarnitines, potentially indicating improved mitochondrial function. LP299v supplementation reduced N-acyl taurines more than four times compared to the placebo, suggesting a substantial impact on restoring biochemical balance. The LP299v-supplemented group showed increased levels of oxidized glycerophosphocholine (oxPC). Additionally, LP299v supplementation led to higher levels of sphingomyelins, L-histidine, D-valine, and p-cresol. LimitationsThis exploratory study suggests potential metabolic pathways influenced by LP299v supplementation. However, the need for further research hinders the ability to draw definitive conclusions. ConclusionsObserved metabolic changes were linked to mitochondrial dysfunction, inflammation, oxidative stress, and gut microbiota disruption. Despite the subtle nature of this alterations, our research successfully detected these differences and connected them to the metabolic disruptions associated with MDD. Our findings emphasise the intricate relationship between metabolism, gut microbiota, and mental health prompting further research into the mechanisms of action of probiotics in MDD treatment.

Mitochondrial dysfunction and oxidative stress in selective fetal growth restriction

IntroductionPlacental dysfunction is the primary cause of selective fetal growth restriction (sFGR), and the specific role of mitochondria remains unclear. This study aims to elucidate mitochondrial functional defects in sFGR placentas and explore the roles of mitochondrial genomic and epigenetic alterations in its pathogenesis. MethodsThe placental villi of MCDA twins with sFGR were collected and the morphology and number of mitochondria were observed by transmission electron microscopy. Meanwhile, the levels of reactive oxygen species (ROS), ATP and oxidative damage markers were assessed. Mitochondrial DNA (mtDNA) copy number detection, targeted sequencing and methylation sequencing were performed. The expression of placental cytochrome c oxidase subunit I (COX I) and mitochondrial long non-coding RNAs (lncRNAs) were evaluated by Western blotting and qPCR. ResultsCompared with placentae from normal fetuses, pronounced mitochondrial damage within cytotrophoblast was revealed in sFGR placentae, alongside augmented mitochondrial number in syncytiotrophoblast. Enhanced oxidative stress in these placentae was evidenced by elevated markers of oxidative damage, accompanied by increased ROS production and diminished ATP generation. In sFGR placentae, a notable rise in mitochondrial copy number and one heterozygous mutation in the MT-RNR2 gene were observed, along with decreased COX Ⅰ levels, increased lncND5, lncND6, lncCyt b, and MDL1 synthesis, and decreased RMRP synthesis. DiscussionFindings collectively confirmed an exacerbation of oxidative stress within sFGR placentae, coinciding with mitochondrial dysfunction, compromised energy production, and ultimately the failure of compensatory mechanisms to restore energy balance, which may result from mutations in the mitochondrial genome and abnormal expression of epigenetic regulatory genes.