Mitochondrial Antioxidant System Research Articles

Berberine Attenuates Acetamiprid Exposure-Induced Mitochondrial Dysfunction and Apoptosis in Rats via Regulating the Antioxidant Defense System.

Acetamiprid (ACMP) is a neonicotinoid insecticide that poses a significant threat to the environment and mankind. Oxidative stress and mitochondrial dysfunction are considered prime contributors to ACMP-induced toxic effects. Meanwhile, berberine (BBR) a natural plant alkaloid, is a topic of interest because of its therapeutic and prophylactic actions. Therefore, this study evaluated the effects of BBR on ACMP-mediated alterations in mitochondrial functions and apoptosis in rat liver tissue. Male Wistar rats were divided into four groups: (I) control, (II) BBR-treated, (III) ACMP-exposed, and (IV) BBR+ACMP co-treated groups. The doses of BBR (150 mg/kg b.wt) and ACMP (1/10 of LD50, i.e., 21.7 mg/kg b.wt) were given intragastrically for 21 consecutive days. The results showed that the administration of ACMP diminished mitochondrial complex activity, downregulated complex I (ND1 and ND2) and complex IV (COX1 and COX4) subunit mRNA expression, depleted the antioxidant defense system, and induced apoptosis in rat liver. BBR pre-treatment significantly attenuated ACMP-induced mitochondrial dysfunction by maintaining mitochondrial complex activity and upregulating ND1, ND2, COX1, and COX4 mRNA expression. BBR reversed ACMP-mediated apoptosis by diminishing Bax and caspase-3 and increasing the Bcl-2 protein level. BBR also improved the mitochondrial antioxidant defense system by upregulating mRNA expression of PGC-1α, MnSOD, and UCP-2 in rat liver tissue. This study is the first to evaluate the protective potential of BBR against pesticide-induced mitochondrial dysfunction in liver tissue. In conclusion, BBR offers protection against ACMP-induced impairment in mitochondrial functions by maintaining the antioxidant level and modulating the apoptotic cascade.

Mitochondria-targeted antioxidant, mitoQ protects hepatic tissue from N-nitrosodiethylamine-induced damage by modulating mitochondrial function and redox status

BackgroundTargeting mitochondrial oxidative stress can be a promising strategy for the prevention of hepatocellular carcinoma (HCC). In the current study, we investigated the modulatory effect of mitochondria-targeted antioxidant, mitoQ against N-nitrosodiethylamine (NDEA)-induced hepatic damage in mouse. MethodsBALB/c mice were administered NDEA (10 mg/kg b. w., single dose, intraperitoneally) and the hepatoprotective effect of mitoQ was studied by administering mitoQ (0.125 mg/kg b. w., orally once a week) to the animals. The administration of mitoQ started two weeks prior the NDEA administration. The animals were sacrificed 24 h following NDEA administration after which the blood samples and hepatic tissues were collected. Serum was used for the estimation of liver injury markers and hepatic tissues were analyzed for histopathological changes, antioxidant defense status, mitochondrial functional status, level of mitochondrial reactive oxygen species (mtROS) and mitochondrial lipid peroxidation (mtLPO). ResultsMitoQ treatment to the NDEA-challenged group normalized liver injury markers, level of mtROS and mtLPO. MitoQ treatment also improved the status of mitochondrial antioxidant defense system, mitochondrial complex enzymes. ConclusionOur findings indicate that mito-Q significantly protected against NDEA-induced hepatic damage by modulating mitochondrial function and redox status which may be one of the causes of its purported chemopreventive effect.

Differences in the Effect of Beta-Hydroxybutyrate on the Mitochondrial Biogenesis, Oxidative Stress and Inflammation Markers in Tissues from Young and Old Rats.

One of the therapeutic approaches to age-related diseases is modulation of body cell metabolism through certain diets or their pharmacological mimetics. The ketogenic diet significantly affects cell energy metabolism and functioning of mitochondria, which has been actively studied in various age-related pathologies. Here, we investigated the effect of the ketogenic diet mimetic beta-hydroxybutyrate (BHB) on the expression of genes regulating mitochondrial biogenesis (Ppargc1a, Nrf1, Tfam), quality control (Sqstm1), functioning of the antioxidant system (Nfe2l2, Gpx1, Gpx3, Srxn1, Txnrd2, Slc6a9, Slc7a11), and inflammatory response (Il1b, Tnf, Ptgs2, Gfap) in the brain, lungs, heart, liver, kidneys, and muscles of young and old rats. We also analyzed mitochondrial DNA (mtDNA) copy number, accumulation of mtDNA damage, and levels of oxidative stress based on the concentration of reduced glutathione and thiobarbituric acid-reactive substances (TBARS). In some organs, aging disrupted mitochondrial biogenesis and functioning of cell antioxidant system, which was accompanied by the increased oxidative stress and inflammation. Administration of BHB for 2 weeks had different effects on the organs of young and old rats. In particular, BHB upregulated expression of genes coding for proteins associated with the mitochondrial biogenesis and antioxidant system, especially in the liver and muscles of young (but not old) rats. At the same time, BHB contributed to the reduction of TBARS in the kidneys of old rats. Therefore, our study has shown that administration of ketone bodies significantly affected gene expression in organs, especially in young rats, by promoting mitochondrial biogenesis, improving the functioning of the antioxidant defense system, and partially reducing the level of oxidative stress. However, these changes were much less pronounced in old animals.

Mitochondrial oxidative stress-mediated ferroptosis as a contributing factor of refrigerated beef tenderness: From mitochondrial biochemistry and proteomics perspective

This study aimed to investigate the mechanism of ferroptosis mediated by mitochondrial oxidative stress and its potential associations with tenderness of beef during refrigeration. Results showed that mitochondrial reactive oxygen species (ROS) reached a maximum at day 3 (116.67 ± 8.50 mg protein), the degree of mitochondrial swelling, mitochondrial membrane permeability increased with the increase of refrigeration time, and mitochondrial free iron content increased significantly (p < 0.05), while mitochondria showed the morphological features of ferroptosis. In addition, the decreased levels of reduced glutathione, total antioxidant capacity and the activity of glutathione peroxidase, and the accumulation of malondialdehyde reflected an imbalance in mitochondrial antioxidant defense system, presenting the physiological characteristics of ferroptosis. Furthermore, mitochondrial TMT quantitative proteomics identified 7 differentially expressed proteins (DEPs) enriched to the ferroptosis pathway, including ACSL1, LOC788801, ACSL4, PRNP, VDAC2, ACSL3 and LPCAT3, which were primarily involved in lipid metabolism pathway and were the major mitochondrial pathway involved in ferroptosis during beef refrigeration. Besides, ROS and lipid peroxidation from mitochondrial oxidative stress-mediated ferroptosis attacked tissue myofibril structure and increased myofibrillar fragmentation index, which promoted the improvement of postmortem meat tenderness. These findings provided new perspectives on the role of mitochondria in cell death and the effect of ferroptosis on muscle tenderization.

Mitochondrial injury induced by triclopyr in the rat liver

The herbicide triclopyr (3,5,6-trichloro-2-pyridinyloxyacetic acid) is already considered an environmental problem due to damage caused by incorrect disposal, leaching, and aerial dispersion, which may pose risks to the environment and human health. Studies have evaluated metabolism, absorption, excretion, and active transport but there is no clear information about its mode of action (MoA) and its cytotoxic action potential remains unknown. In this context, mitochondria have been used to assess the toxicity of xenobiotics, for this reason, to identify the toxic mechanism of triclopyr, hepatic mitochondria from Wistar rats were exposed in vitro to different concentrations of triclopyr (0.5–500 µM). There was neither formation/accumulation of reactive oxygen and nitrogen species, nor lipid peroxidation or changes in the mitochondrial antioxidant system, in addition to proper functioning of oxidative phosphorylation and ATP production. Changes were found in NAD(P)H oxidation, membrane potential dissipation and mitochondrial calcium gradient. These results demonstrate that mitochondria suffer damage related to their bioenergetics and redox status but not to their structure when exposed to concentrations of triclopyr considered higher than those described as found in the environment so far. Highlights Triclopyr has a low mitochondrial uncoupling potential. The damage caused to the bioenergetics and redox state of the mitochondria is related to concentrations considered higher than those found in the environment. Even at high concentrations, triclopyr was not able to change the structure of the organelle after exposure. Oxidative phosphorylation and ATP production were not impaired after exposure. NAD(P)H oxidation resulted in potential membrane dissipation and mitochondrial calcium gradient dissipation. Triclopyr does not have RONS-forming properties, as well as it does not peroxide membrane lipids, it preserves membrane sulfhydryl groups and maintains the normality of the GSH/GSSG ratio.

Climate change consequences on the systemic heart of female Octopus maya: oxidative phosphorylation assessment and the antioxidant system.

There is evidence that indicates that temperature modulates the reproduction of the tropical species Octopus maya, through the over- or under-expression of many genes in the brain. If the oxygen supply to the brain depends on the circulatory system, how temperature affects different tissues will begin in the heart, responsible for pumping the oxygen to tissues. The present study examines the impact of heat stress on the mitochondrial function of the systemic heart of adult O. maya. The mitochondrial metabolism and antioxidant defense system were measured in the systemic heart tissue of female organisms acclimated to different temperatures (24, 26, and 30°C). The results show that acclimation temperature affects respiratory State 3 and State 4o (oligomycin-induced) with higher values observed in females acclimated at 26°C. The antioxidant defense system is also affected by acclimation temperature with significant differences observed in superoxide dismutase, glutathione S-transferase activities, and glutathione levels. The results suggest that high temperatures (30°C) could exert physical limitations on the circulatory system through the heart pumping, affecting nutrient and oxygen transport to other tissues, including the brain, which exerts control over the reproductive system. The role of the cardiovascular system in supporting aerobic metabolism in octopus females is discussed.

2,4,6-trinitrotoluene causes mitochondrial toxicity in Caenorhabditis elegans by affecting electron transport

As a typical energetic compound widely used in military activities, 2,4,6-trinitrotoluene (TNT) has attracted great attention in recent years due to its heavy pollution and wide distribution in and around the training facilities, firing ranges, and demolition sites. However, the subcellular targets and the underlying toxic mechanism of TNT remain largely unknown. In this study, we explored the toxic effects of TNT biological reduction on the mitochondrial function and homeostasis in Caenorhabditis elegans (C. elegans). With short-term exposure of L4 larvae, 10–1000 ng/mL TNT reduced mitochondrial membrane potential and adenosine triphosphate (ATP) content, which was associated with decreased expression of specific mitochondrial complex involving gas-1 and mev-1 genes. Using fluorescence-labeled transgenic nematodes, we found that fluorescence expression of sod-3 (muls84) and gst-4 (dvls19) was increased, suggesting that TNT disrupted the mitochondrial antioxidant defense system. Furthermore, 10 ng/mL TNT exposure increased the expression of the autophagy-related gene pink-1 and activated mitochondrial unfolded protein response (mt UPR), which was indicated by the increased expression of mitochondrial stress activated transcription factor atfs-1, ubiquitin-like protein ubl-5, and homeobox protein dve-1. Our findings demonstrated that TNT biological reduction caused mitochondrial dysfunction and the development of mt UPR protective stress responses, and provided a basis for determining the potential risks of energetic compounds to living organisms.

Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases.

Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function. In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich's Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR's role as a promising therapeutic target in combating these devastating disorders.

Advances in exercise to alleviate sarcopenia in older adults by improving mitochondrial dysfunction.

Sarcopenia is a chronic degenerative disease affecting primarily older adults. A growing aging population is gradually increasing the number of patients suffering from sarcopenia, placing increasing financial pressure on patients' families and society in general. There is a strong link between mitochondrial dysfunction and sarcopenia pathogenesis. As a result, treating sarcopenia by improving mitochondrial dysfunction is an effective strategy. Numerous studies have demonstrated that exercise has a positive effect on mitochondrial dysfunction when treating sarcopenia. Exercise promotes mitochondrial biogenesis and mitochondrial fusion/division to add new mitochondria or improve dysfunctional mitochondria while maintaining mitochondrial calcium homeostasis, mitochondrial antioxidant defense system, and mitochondrial autophagy to promote normal mitochondrial function. Furthermore, exercise can reduce mitochondrial damage caused by aging by inhibiting mitochondrial oxidative stress, mitochondrial DNA damage, and mitochondrial apoptosis. Exercise effectiveness depends on several factors, including exercise duration, exercise intensity, and exercise form. Therefore, Moderate-intensity exercise over 4weeks potentially mitigates sarcopenia in older adults by ameliorating mitochondrial dysfunction. HIIT has demonstrated potential as a viable approach to addressing sarcopenia in aged rats. However, further investigation is required to validate its efficacy in treating sarcopenia in older adults.

Nicotinamide enhances osteoblast differentiation through activation of the mitochondrial antioxidant defense system

Although the normal physiological level of oxidative stress is beneficial for maintaining bone homeostasis, imbalance between reactive oxygen species (ROS) production and antioxidant defense can cause various bone diseases. The purpose of this study was to determine whether nicotinamide (NAM), an NAD+ precursor, can support the maintenance of bone homeostasis by regulating osteoblasts. Here, we found that NAM enhances osteoblast differentiation and mitochondrial metabolism. NAM increases the expression of antioxidant enzymes, which is due to increased FOXO3A transcriptional activity via SIRT3 activation. NAM has not only a preventive effect against weak and chronic oxidative stress but also a therapeutic effect against strong and acute exposure to H2O2 in osteoblast differentiation. Collectively, the results indicate that NAM increases mitochondrial biogenesis and antioxidant enzyme expression through activation of the SIRT3-FOXO3A axis, which consequently enhances osteoblast differentiation. These results suggest that NAM could be a potential preventive or therapeutic agent for bone diseases caused by ROS.

CISPLATIN - AN OVERVIEW OF ITS EFFICIENCY AND TOXICITY

Cisplatin is the first heavy metal compound that has been found to possess antineoplastic activity. It is effective in treating testicular, ovarian, head and neck, bladder, cervical, esophageal tumors, and small cell lung carcinoma. Approximately 1% of cisplatin that enters the cell interacts with DNA, forming DNA-cisplatin bonds. Both apoptosis and necrosis can be found in the same population of cells exposed to cisplatin, and the mode of cell death depends on the cisplatin concentration and metabolic state of the target cell. In the bloodstream, the platinum component of cisplatin binds to the blood's proteins (hemoglobin, albumin and transferrin), and other significant portion binds to the glutathione and other cysteine-rich biomolecules. Cisplatin impairs the mitochondrial and cell antioxidant defense system (decreases GSH, NADPH levels, GCH/GSSG ratio, and increases GSSG levels) leading to oxidative stress. There are three main mechanisms of cell resistance to cisplatin: (1) enhanced repair of cisplatin-induced DNA lesions, (2) decrease in uptake and/or increase in efflux and (3) inactivation of cisplatin intracellularly. The usage of cisplatin is limited due to its toxicity and side effects, which include neurotoxicity (numbness and tingling, paresthesia, reduced deep tendon reflexes), nephrotoxicity (renal insufficiency, hypomagnesemia), ototoxicity (tinnitus and bilateral high-frequency hearing loss), cardiotoxicity (changes in electric heart activity, congestive heart failure), gastrotoxicity (nausea, vomiting, and dyspepsia), etc. So far, there has been no effective, clinically administered, therapy for cisplatin-induced toxicity.

Melatonin attenuates bisphenol A-induced colon injury by dual targeting mitochondrial dynamics and Nrf2 antioxidant system via activation of SIRT1/PGC-1α signaling pathway

Industrial advancement has led to an increase in the production and usage of bisphenol A (BPA), thereby resulting in serious environmental pollution problems. BPA ingestion causes multiorgan toxicity. However, the exact mechanism underlying BPA-induced colon damage remains elusive. Moreover, no safe treatment is available to alleviate BPA-induced colon injury. Therefore, the in vivo and in vitro approaches were employed to detect the protective effects of melatonin (MT) on BPA-induced colon injury and to determine the underpinning molecular mechanisms. MT treatment of mice and the colonic epithelial cells NCM460 alleviated BPA-induced colon damage by inhibiting the mitochondrial dynamic imbalance, enhancing mitochondrial respiratory chain (MRC) complexes expression, reducing reactive oxygen species (ROS) production, and suppressing apoptosis and necroptosis. MT upregulated the proteins level of silent information regulator 1 (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which further increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and the downstream antioxidant target genes heme oxygenase-1 (HO-1) and NAD(P)H quinone redox enzyme-1 (NQO1). Treatment with the SIRT1 inhibitor EX527 effectively reversed the MT-induced upregulation of the aforementioned protein levels. Thus, the MT-activated Sirt1/PGC-1α signaling pathway restored the mitochondrial dynamic balance and activated the Nrf2 antioxidant axis to attenuate BPA-induced colon injury. These results demonstrate that MT supplementation may potentially mitigate BPA toxicity.

Carboxylated ε-Poly-L-Lysine Supplementation of the Freezing Extender Improves the Post-Thawing Boar Sperm Quality.

Frozen boar sperm is used on a minimal scale in consequence of the cryo-injuries induced by biochemical and physical modifications during the freezing and thawing processes. The present study investigates whether the addition of carboxylated ε-poly-L-lysine (CPLL) to the freezing medium could improve post-thaw boar sperm quality or not. Boar sperm was diluted with freezing medium contained different doses of carboxylated ε-poly-L-lysine (0, 0.125%, 0.25%, 0.5%, and 1%; v/v). The motility patterns, membrane integrity, acrosome integrity, mitochondrial membrane potential, NADH-CoQ activity, ATP level, malondialdehyde (MDA) level, and antioxidant defense system, as well as apoptosis in post-thaw boar sperm, were measured. It was observed that 0.25% CPLL treatment significantly improved the post-thaw boar sperm total motility, progressive motility, straight-linear velocity (VSL), curvilinear velocity (VCL), average path velocity (VAP), linearity (LIN), straightness (STR), membrane integrity, and acrosome integrity. Interestingly, the addition of CPLL also significantly increased the post-thaw sperm mitochondrial membrane potential, NADH-CoQ activity, and ATP level. Moreover, post-thaw boar sperm catalase (CAT) activity, glutathione peroxidase (GPx) activity, and superoxide dismutase (SOD) activity were increased with the addition of CPLL from 0.125% to 0.5% concentration levels. Furthermore, reduction of post-thaw sperm MDA level and apoptosis in 0.25% CPLL treatment was also observed. Those observations suggested that the addition of 0.25% CPLL to the freezing medium increased post-thaw boar sperm quality by protecting sperm mitochondrial function and antioxidant defense system. These findings provided novel insights that CPLL can be used as an efficient cryoprotectant to improve the post-thaw boar sperm quality during cryopreservation.

Adiponectin/AdiopR1 signaling prevents mitochondrial dysfunction and oxidative injury after traumatic brain injury in a SIRT3 dependent manner

Mitochondrial dysfunction and oxidative injury, which contribute to worsening of neurological deficits and poor clinical outcomes, are hallmarks of secondary brain injury after TBI. Adiponectin (APN), beyond its well-established regulatory effects on metabolism, is also essential for maintaining normal brain functions by binding APN receptors that are ubiquitously expressed in the brain. Currently, the significance of the APN/APN receptor (AdipoR) signaling pathway in secondary injury after TBI and the specific mechanisms have not been conclusively determined. In this study, we found that APN knockout aggravated brain functional deficits, increased brain edema and lesion volume, and exacerbated oxidative stress as well as apoptosis after TBI. These effects were significantly alleviated after APN receptor agonist (AdipoRon) treatment. Moreover, we found that AdipoR1, rather than AdipoR2, mediated the protective effects of APN/AdipoR signaling against oxidative stress and brain injury after TBI. In neuron-specific AdipoR1 knockout mice, mitochondrial damage was more severe after TBI, indicating a potential association between APN/AdipoR1 signaling inactivation and mitochondrial damage. Mechanistically, neuron-specific knockout of SIRT3, the most important deacetylase in the mitochondria, reversed the neuroprotective effects of AdipoRon after TBI. Then, PRDX3, a critical antioxidant enzyme in the mitochondria, was identified as a vital downstream target of the APN/SIRT3 axis to alleviate oxidative injury after TBI. Finally, we revealed that APN/AdipoR1 signaling promotes SIRT3 transcription by activating the AMPK-PGC pathway. In conclusion, APN/AdipoR1 signaling plays a protective role in post-TBI oxidative damage by restoring the SIRT3-mediated mitochondrial homeostasis and antioxidant system.

Oxidative stress impairs the meat quality of broiler by damaging mitochondrial function, affecting calcium metabolism and leading to ferroptosis.

ObjectiveThis work was conducted to investigate the effects of oxidative stress on meat quality, mitochondrial function, calcium metabolism and ferroptosis of broilers.MethodsIn this study, a total of 144 one-day-old male Ross 308 chicks were divided into 3 groups (control group, saline group, and hydrogen peroxide [H2O2] group) with 6 replicates of 8 broilers each. The study lasted for 42 d. The broilers in the saline and H2O2 groups were intraperitoneally injected with 0.75% saline and 10.0% H2O2 on the 16th and 37th day of the experimental period respectively, the injection volumes were 1.0 mL/kg of broiler body weight. On the 42nd day of the experimental period, two chicks were randomly selected from each cage, a total of thirty-six chicks were stunned by electric shock and slaughtered to collect breast muscle samples.ResultsThe H2O2 exposure reduced pH value, increased drip loss and shear force of breast meat (p<0.05), impaired the ultrastructure and function of mitochondria. The H2O2 exposure damaged the antioxidant system in mitochondria, excessive reactive oxygen species carbonylation modified calcium channels on mitochondria, which impaired the activities of key enzymes on calcium channel, resulted in the increased calcium concentration in cytoplasm and mitochondria (p<0.05). In addition, the H2O2 exposure increased the iron content and lipid peroxidation (p<0.05), which induced ferroptosis.ConclusionOxidative stress could impair meat quality by causing mitochondrial dysfunction, resulting in calcium metabolism disorder and ferroptosis.

Abstract 241: Nicotinamide Nucleotide Transhydrogenase Regulates Mitochondrial Function And Oxldl Induced Macrophage Endothelial Interaction.

Atherosclerosis is a chronic inflammatory disease effecting large and medium sized arteries that leads to the buildup of plaque that contributes to myocardial infraction, stroke, and other pathologies. Mounting evidence has identified mitochondrial reactive oxygen species (ROS) as a key contributor to plaque formation and progression. A inner mitochondrial membrane enzyme Nicotinamide nucleotide transhydrogenase (NNT) sustains NADPH pools required for the mitochondrial antioxidant systems. We have observed that the expression of NNT is decreased in severe human atherosclerotic plaques leading us to hypothesize that the loss of NNT contributes to increased mitochondrial ROS and drives the progression of atherosclerosis by enhancing endothelial and vascular dysfunction. Utilizing AAV/PCSK9 and HFD induced models of early and late-stage atherosclerosis, we found that NNT knockout (NNT KO) mice display significantly increased VCAM-1 expression in aortic endothelial cells during early atherosclerosis and significantly larger necrotic cores in late-stage atherosclerosis. Additionally, NNT KO mice displayed a significantly thinner fibrous cap in late-stage plaques. Similar results were observed in vitro where the loss of NNT in human aortic endothelial cells exacerbated oxLDL induced VCAM-1 expression that was associated with decreased mitochondrial NADPH levels, glutathione peroxidase (Gpx2) activity, and increased H 2 O 2 production. The observed increase in necrotic core area in NNT KO mice is suggestive of increased inflammatory cell recruitment to the plaque. Furthermore, bone marrow derived macrophages (BMDM) from NNT KO mice display decreased lipid content, poor lipid uptake and a predisposition to differentiate into a proinflammatory M1 phenotype. Based on these studies, we conclude that the loss of NNT contributes to unstable plaques with large necrotic cores, mitochondrial ROS driven endothelial dysfunction, increased inflammatory cell recruitment, and enhanced M1 macrophage activity. The novel relationship between vascular NNT expression and plaque severity in human samples implicates NNT as a novel clinical target in atherosclerosis.

Neuroprotective effect of hesperidin and its combination with coenzyme Q10 on an animal model of ketamine-induced psychosis: behavioral changes, mitochondrial dysfunctions, and oxidative stress

BackgroundPsychosis is a complex mental illness divided by positive symptoms, negative symptoms, and cognitive decline. Clinically available medicines are associated with some serious side effects which limit their use. Treatment with flavonoids has been associated with delayed onset and development, decreased risk, or increased improvement of various neuropsychiatric disorders including psychosis with negligible side effects. Therefore, the present study was aimed to investigate the protective effects of hesperidin (flavonoid) alone or its combination with coenzyme Q10 against ketamine-induced psychotic symptoms in mice.ResultsKetamine (50 mg/kg, i.p.) was given for 21 days to induce psychosis in Laca mice of either sex. Locomotor activity and stereotypic behaviors, immobility duration (forced swim test), and increased transfer latency (elevated plus maze) were performed to test the effect of hesperidin (50 mg/kg, 100 mg/kg, 200 mg/kg, p.o.) and coenzyme Q10 (20 mg/kg, 40 mg/kg, p.o.) and combination of hesperidin + coenzyme Q10 followed by biochemical and mitochondrial complexes assays. For 21 days, ketamine (50 mg/kg, i.p.) administration significantly produced increased locomotor activity and stereotypic behaviors (positive symptoms), increased immobility duration (negative symptoms) and cognitive deficits (increases transfer latency) weakens oxidative defense and mitochondrial function. Further, 21 days’ administration of hesperidin and coenzyme Q10 significantly reversed the ketamine-induced psychotic behavioral changes and biochemical alterations and mitochondrial dysfunction in the discrete areas (prefrontal cortex and hippocampus) of mice brains. The potential effect of these drugs was comparable to olanzapine treatment. Moreover, the combination of hesperidin with coenzyme Q10 and or a combination of hesperidin + coenzyme Q10 + olanzapine treatment did not produce a significant effect compared to their per se effect in ketamine-treated animals.ConclusionsThe study revealed that hesperidin alone or in combination with coenzyme Q10 could reduce psychotic symptoms and improve mitochondrial functions and antioxidant systems in mice, suggesting neuroprotective effects against psychosis.

Hydroxychloroquine inhibits the mitochondrial antioxidant system in activated T cells

Although hydroxychloroquine (HCQ) has long been used to treat autoimmune diseases, its mechanism of action remains poorly understood. In CD4 T-cells, we found that a clinically relevant concentration of HCQ inhibited the mitochondrial antioxidant system triggered by TCR crosslinking, leading to increased mitochondrial superoxide, impaired activation-induced autophagic flux, and reduced proliferation of CD4 T-cells. In antigen-presenting cells, HCQ also reduced constitutive activation of the endo-lysosomal protease legumain and toll-like receptor 9, thereby reducing cytokine production, but it had little apparent impact on constitutive antigen processing and peptide presentation. HCQ's effects did not require endo-lysosomal pH change, nor impaired autophagosome-lysosome fusion. We explored the clinical relevance of these findings in patients with celiac disease-a prototypic CD4 T-cell-mediated disease-and found that HCQ limits exvivo antigen-specific Tcell responses. We report a T-cell-intrinsic immunomodulatory effect from HCQ and suggest potential re-purposing of HCQ for celiac disease.

Mitochondrial Management of Reactive Oxygen Species

Mitochondria in aerobic eukaryotic cells are both the site of energy production and the formation of harmful species, such as radicals and other reactive oxygen species, known as ROS. They contain an efficient antioxidant system, including low-molecular-mass molecules and enzymes that specialize in removing various types of ROS or repairing the oxidative damage of biological molecules. Under normal conditions, ROS production is low, and mitochondria, which are their primary target, are slightly damaged in a similar way to other cellular compartments, since the ROS released by the mitochondria into the cytosol are negligible. As the mitochondrial generation of ROS increases, they can deactivate components of the respiratory chain and enzymes of the Krebs cycle, and mitochondria release a high amount of ROS that damage cellular structures. More recently, the feature of the mitochondrial antioxidant system, which does not specifically deal with intramitochondrial ROS, was discovered. Indeed, the mitochondrial antioxidant system detoxifies exogenous ROS species at the expense of reducing the equivalents generated in mitochondria. Thus, mitochondria are also a sink of ROS. These observations highlight the importance of the mitochondrial antioxidant system, which should be considered in our understanding of ROS-regulated processes. These processes include cell signaling and the progression of metabolic and neurodegenerative disease.

Mitoquinol mesylate (MITOQ) attenuates diethyl nitrosamine-induced hepatocellular carcinoma through modulation of mitochondrial antioxidant defense systems.

Diethyl nitrosamine (DEN) induced cirrhosis-hepatocellular carcinoma (HCC) model associates cancer progression with oxidative stress and mitochondrial dysfunction. This study investigated the effects of mitoquinol mesylate (MitoQ), a mitochondrial-targeted antioxidant on DEN-induced oxidative damage in HCC Wistar rats. Fifty male Wistar rats were randomly divided into five groups. Healthy control, DEN, and MitoQ groups were orally administered exactly 10mg/kgof distilled water, DEN, and MitoQ, respectively for 16weeks. Animals in the MitoQ + DEN group were pre-treated with MitoQ for a week followed by co-administration of 10mg/kg each of MitoQ and DEN. DEN + MitoQ group received DEN for 8weeks, then co-administration of 10mg/kg each of DEN and MitoQ till the end of 16th week. Survival index, tumour incidence, hematological profile, liver function indices, lipid profile, mitochondrial membrane composition, mitochondrial respiratory enzymes, and antioxidant defense status in both mitochondrial and post-mitochondrial fractions plus expression of antioxidant genes were assessed. In MitoQ + DEN and DEN + MitoQ groups, 80% survival occurred while tumour incidence decreased by 60% and 40% respectively, compared to the DEN-only treated group. Similarly, MitoQ-administered groups showed a significant (p<0.05) decrease in the activities of liver function enzymes while hemoglobin concentration, red blood cell count, and packed cell volume were significantly elevated compared to the DEN-only treated group. Administration of MitoQ to the DEN-intoxicated groups successfully enhanced the activities of mitochondrial F1F0-ATPase and succinate dehydrogenase; and up-regulated the expression and activities of SOD2, CAT, and GPx1. Macroscopic and microscopic features indicated a reversal of DEN-induced hepatocellular degeneration in the MitoQ + DEN and DEN + MitoQ groups. These data revealed that MitoQ intervention attenuated DEN-induced oxidative stress through modulation of mitochondrial antioxidant defense systems and alleviated the burden of HCC as a chemotherapeutic agent.