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Mitochondrial dysfunction and excessive reactive oxygen species production contributes to the pathophysiology of aging. Coenzyme Q10 is thought to protect mitochondria from oxidative damage; thus, mitoquinone was developed as mitochondria‐targeted analogue with similar antioxidant activity. Mitoquinone is the oxidized form of mitoquinol. Mitoquinone/mitoquinol mesylate has been proposed as a food ingredient. As part of the safety analysis, we performed genotoxicity assays and a 39‐week toxicity study to determine overall toxicity potential. Mitoquinone mesylate showed no evidence of genotoxic potential in two in vitro assays, bacterial reverse mutation and human lymphocyte chromosome aberration, nor in the in vivo micronucleus test in rats. In the 39‐week study in dogs, there were no findings observed, which were considered to represent adverse systemic toxicity; therefore, the high dose level (40 mg/kg/day) was considered the NOAEL. The principal findings in this study were fecal disturbances and vomiting. These findings were considered to be due to a local, possibly irritant effect of the test substance on the gastrointestinal tract and were not considered adverse as there were no impacts on clinical or histopathology. This highest dose exceeds the expected daily human intake more than 100‐fold. Data from well‐designed clinical trials actively collecting safety endpoints corroborate that 20 mg/day can be safely consumed and is not likely to result in significant gastrointestinal complaints. These results support the conclusion that the use of mitoquinone/mitoquinol mesylate as a food ingredient is safe. Mitochondrial dysfunction and excessive reactive oxygen species production contributes to the pathophysiology of aging. Mitoquinone/mitoquinol was developed as mitochondria‐targeted analogue to Coenzyme Q10 with similar antioxidant activity but is not a substrate for oxidative phosphorylation. Studies show it is not genotoxic and had a NOAEL of 40 mg/kg/day in a 39‐week study. This dose exceeds the expected daily human intake more than 100‐fold. These results support the conclusion that the use of mitoquinone/mitoquinol mesylate as a food ingredient is safe. [ABSTRACT FROM AUTHOR]

Simple Summary: When a couple faces infertility challenges like sperm motility issues, they often visit fertility clinics for assistance. Poor sperm motility can delay fertilization, making natural conception difficult. In an andrology laboratory, embryologists test the semen sample. Before assisted reproduction procedures, embryologists usually perform a group of steps to prepare the semen sample and to isolate the best sperms. These technical steps might harm the sperms, because they become susceptible to something so called; oxidative stress, which occurs when too many harmful molecules called free radicals accumulate in the test tube, leading to cell damage and death. A group of chemicals called antioxidants can neutralize these free radicals. The researchers in this study investigated the therapeutic effects of Mitoquinone, which is a mitochondria-targeted antioxidant, on the motility of human sperms exposed to oxidative stress during in vitro procedures. Mitoquinone as an antioxidant might have therapeutic potential for sperms' oxidative-damage-associated disorders. This investigation paves the route for future research to confirm the beneficial role of Mitoquinone supplementation in improving and enhancing sperm quality during in vitro processes in the andrology laboratories. The preparation of human sperm in an andrology laboratory subjects it to oxidative stress. Reactive oxygen species are produced by mitochondria, making it susceptible to oxidative damage; hence, mitochondria-targeted antioxidants like Mitoquinone (MitoQ) might have therapeutic potential for oxidative-damage-associated disorders. The current research aims to establish whether MitoQ has any positive effects during in vitro preparation of fresh human sperm. Viability and motility are evaluated to determine the effective MitoQ concentration and to assess whether MitoQ supplementation is affected by sperm concentration by incubating normospermia semen samples at 37 °C for 2 h and 4 h, respectively. The effect of semen centrifugation following supplementation of 20 × 106 sperm/mL with 200 nM MitoQ is also assessed by measuring viability, motility and sperm DNA fragmentation. The best sperm motility is achieved after 2 h of incubation with 200 nM MitoQ at 37 °C. Sperm concentration of 20 × 106 sperm/mL is the best concentration where 200 nM MitoQ works efficiently. For semen centrifugation at 300× g for 20 min, supplementation with 200 nM MitoQ shows higher sperm motility. The current results demonstrate that MitoQ supplementation during in vitro human semen preparation procedures positively affects fresh sperm motility without affecting viability or increasing DNA fragmentation. [ABSTRACT FROM AUTHOR]

Oxygen is essential for aerobic life on earth but it is also the origin of harmful reactive oxygen species (ROS). Ubiquinone is par excellence the endogenous cellular antioxidant, but a very hydrophobic one. Because of that, other molecules have been envisaged, such as idebenone (IDE) and mitoquinone (MTQ), molecules having the same redox active benzoquinone moiety but higher solubility. We have used molecular dynamics to determine the location and interaction of these molecules, both in their oxidized and reduced forms, with membrane lipids in a membrane similar to that of the mitochondria. Both IDE and reduced IDE (IDOL) are situated near the membrane interface, whereas both MTQ and reduced MTQ (MTQOL) locate in a position adjacent to the phospholipid hydrocarbon chains. The quinone moieties of both ubiquinone 10 (UQ10) and reduced UQ10 (UQOL10) in contraposition to the same moieties of IDE, IDOL, MTQ and MTQOL, located near the membrane interphase, whereas the isoprenoid chains remained at the middle of the hydrocarbon chains. These molecules do not aggregate and their functional quinone moieties are located in the membrane at different depths but near the hydrophobic phospholipid chains whereby protecting them from ROS harmful effects. [Display omitted] • We simulate molecular dynamics of the location and interaction of idebenone, mitoquinone and ubiquinone 10, in both their oxidized and reduced form, in a membrane. • Idebenone and reduced idebenone are near the membrane interface, whereas mitoquinone and reduced mitoquinone locate adjacent to the phospholipid hydrocarbon chains. • The quinone moieties of idebenone and mitoquinone, in their both forms, locate at the middle of the palisade structure of the membrane, whereas their isoprenoid chains remain near the phospholipid interphase. • The quinone moieties of ubiquinone 10, in its both forms, are near the phospholipid interphase whereas the isoprenoid chains remained at the middle of the hydrocarbon chains. [ABSTRACT FROM AUTHOR]

Abstract Background Primary osteoarthritis (OA) occurs without identifiable underlying causes such as previous injuries or specific medical conditions. Age is a major contributing factor to OA, and as one ages, various joint tissues undergo gradual change, including degeneration of the articular cartilage, alterations in subchondral bone (SCB) morphology, and inflammation of the synovium. Methods We investigated the prevalence of primary OA in aged, genetically diverse UM-HET3 mice. Articular cartilage (AC) integrity and SCB morphology were assessed in 182 knee joints of 22-25 months old mice using the Osteoarthritis Research Society International (OARSI) scoring system and micro-CT, respectively. Additionally, we explored the effects of methylene blue (MB) and mitoquinone (MitoQ), two agents that affect mitochondrial function, on the prevalence and progression of OA during aging. Results Aged UM-HET3 mice showed a high prevalence of primary OA in both sexes. Significant positive correlations were found between cumulative AC (cAC) scores and synovitis in both sexes, and osteophyte formation in female mice. Ectopic chondrogenesis did not show significant correlations with cAC scores. Significant direct correlations were found between AC scores and inflammatory markers in chondrocytes, including matrix metalloproteinase-13, inducible nitric oxide synthase, and the NLR family pyrin domain containing-3 inflammasome in both sexes, indicating a link between OA severity and inflammation. Additionally, markers of cell cycle arrest, such as p16 and β-galactosidase, also correlated with AC scores. In male mice, no significant correlations were found between SCB morphology traits and cAC scores, while in female mice, significant correlations were found between cAC scores and tibial SCB plate bone mineral density. Notably, MB and MitoQ treatments influenced the disease's progression in a sex-specific manner. MB treatment significantly reduced cAC scores at the medial knee joint, while MitoQ treatment reduced cAC scores, but these did not reach significance. Conclusions Our study provides comprehensive insights into the prevalence and progression of primary OA in aged UM-HET3 mice, highlighting the sex-specific effects of MB and MitoQ treatments. The correlations between AC scores and various pathological factors underscore the multifaceted nature of OA and its association with inflammation and subchondral bone changes.

Inorganic arsenic is a well-established environmental toxicant linked to acute liver injury, fibrosis, and cancer. While oxidative stress, pyroptosis, and ferroptosis are known contributors, the role of PTEN-induced kinase 1 (PINK1)-mediated mitophagy in arsenic-induced hepatic immunotoxicity remains underexplored. Our study revealed that acute arsenic exposure prompts differentiation of hepatic dendritic cells (DCs) and T helper (Th) 1, Th2, Th17, and regulatory T (Treg) cells, alongside increased transcription factors and cytokines. Inorganic arsenic triggered liver redox imbalance, leading to elevated alanine transaminase (ALT), hydrogen peroxide (H2O2), malondialdehyde (MDA), and activation of nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) pathway. PINK1-mediated mitophagy was initiated, and its inhibition exacerbates H2O2 accumulation while promoting DCs/Th1/Th2/Treg differentiation in the liver of arsenic-exposed mice. Mitoquinone (MitoQ) pretreatment relieved arsenic-induced acute liver injury and immune imbalance by activating Nrf2/HO-1 and PINK1-mediated mitophagy. To our knowledge, this is the first report identifying PINK1-mediated mitophagy as a protective factor against inorganic arsenic-induced hepatic DCs/Th1/Th2 differentiation. This study has provided new insights on the immunotoxicity of inorganic arsenic and established a foundation for exploring preventive and therapeutic strategies targeting PINK1-mediated mitophagy in acute liver injury. Consequently, the application of mitochondrial antioxidant MitoQ may offer a promising treatment for the metalloid-induced acute liver injury.

The preparation of human sperm in an andrology laboratory subjects it to oxidative stress. Reactive oxygen species are produced by mitochondria, making it susceptible to oxidative damage; hence, mitochondria-targeted antioxidants like Mitoquinone (MitoQ) might have therapeutic potential for oxidative-damage-associated disorders. The current research aims to establish whether MitoQ has any positive effects during in vitro preparation of fresh human sperm. Viability and motility are evaluated to determine the effective MitoQ concentration and to assess whether MitoQ supplementation is affected by sperm concentration by incubating normospermia semen samples at 37 °C for 2 h and 4 h, respectively. The effect of semen centrifugation following supplementation of 20 × 106 sperm/mL with 200 nM MitoQ is also assessed by measuring viability, motility and sperm DNA fragmentation. The best sperm motility is achieved after 2 h of incubation with 200 nM MitoQ at 37 °C. Sperm concentration of 20 × 106 sperm/mL is the best concentration where 200 nM MitoQ works efficiently. For semen centrifugation at 300× g for 20 min, supplementation with 200 nM MitoQ shows higher sperm motility. The current results demonstrate that MitoQ supplementation during in vitro human semen preparation procedures positively affects fresh sperm motility without affecting viability or increasing DNA fragmentation.

Mitoquinone (MitoQ), a mitochondria-targeted antioxidant, has been used to treat several diseases. The present study aimed to investigate the therapeutic effects of MitoQ in benign prostatic hyperplasia (BPH) models and their underlying molecular mechanisms. In this study, we determined that MitoQ inhibited dihydrotestosterone (DHT)-induced cell proliferation and mitochondrial ROS by inhibiting androgen receptor (AR) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) signaling in prostate epithelial cells. Molecular modeling revealed that DHT may combine with AR and NLRP3, and that MitoQ inhibits both AR and NLRP3. AR and NLRP3 downregulation using siRNA showed the linkage among AR, NLRP3, and MitoQ. MitoQ administration alleviated pathological prostate enlargement and exerted anti-proliferative and antioxidant effects by suppressing the AR and NLRP3 signaling pathways in rats with BPH. Hence, our findings demonstrated that MitoQ is an inhibitor of NLPR3 and AR and a therapeutic agent for BPH treatment.

Ferroptosis is a form of oxidative cell death that is characterized by enhanced lipid peroxidation and mitochondrial impairment. The enzymes acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase (LPCAT) play an essential role in the biosynthesis of polyunsaturated fatty acid (PUFA)-containing phospholipids, thereby providing the substrates for lipid peroxidation and promoting ferroptosis. To examine the impact of mitochondria in ACSL4/LPCAT2-driven ferroptosis, HEK293T cells overexpressing ACSL4 and LPCAT2 (OE) or empty vector controls (LV) were exposed to 1S, 3R-RSL3 (RSL3) for induction of ferroptosis. The ACSL4/LPCAT2 overexpression resulted in higher sensitivity against RSL3-induced cell death compared to LV-transfected controls. Moreover, mitochondrial parameters such as mitochondrial reactive oxygen species (ROS) formation, mitochondrial membrane potential, and mitochondrial respiration deteriorated in the OE cells, supporting the conclusion that mitochondria play a significant role in ACSL4/LPCAT2-driven ferroptosis. This was further confirmed through the protection of OE cells against RSL3-mediated cell death by the mitochondrial ROS scavenger mitoquinone (MitoQ), which exerted protection via antioxidative properties rather than through previously reported metabolic effects. Our findings implicate that mitochondrial ROS production and the accompanying organelle disintegration are essential for mediating oxidative cell death initiated through lipid peroxidation in ferroptosis. [ABSTRACT FROM AUTHOR]

• Mitoquinone was added to the extender before freezing stallion sperm. • Mitoquinone slightly improved the quality of frozen-thawed stallion sperm. • Mitoquinone increased sperm motility at a concentration of 25 nM. • Mitoquinone at a concentration of 200nM negatively affected motility and viability. This study aimed to investigate the effect of mitochondria-targeted antioxidants (Mitoquinone, MitoQ) on the quality of frozen-thawed stallion semen. Semen samples collected from three fertile stallions aged 10 - 13 years, were filtered, centrifuged in a skimmed milk-based extender, and diluted to a final concentration of 50 × 106 sperm/mL in freezing medium. Diluted semen was divided into five experimental groups supplemented with MitoQ at concentrations of 0 (control), 25, 50, 100, and 200 nM and then subjected to freezing after cooling and equilibration. After thawing, semen was evaluated for motility and kinetics at different time points. Sperm viability, plasma membrane, acrosome, DNA integrity, mitochondrial membrane potential, apoptosis, and intracellular reactive oxygen species (ROS) concentrations were evaluated. The results revealed that MitoQ at concentrations of 25, 50, and 100 nM improved (P< 0.01) the total sperm motility after 30 minutes of incubation. In addition, 25 nM MitoQ improved the sperm amplitude of lateral head displacement values (P< 0.01) after 30 minutes of incubation. Conversely, negative effects on sperm motility, kinetics, and viability were observed with the highest tested concentration of MitoQ (200 nM). The various concentrations of MitoQ did not affect the plasma membrane, acrosome, and DNA integrity, or the mitochondrial membrane potential and intracellular ROS concentrations. In conclusion, supplementation of MitoQ during cryopreservation, had a mild positive effect on sperm motility and kinetics especially at a concentration of 25 nM, while the highest concentration (200nM) has a detrimental effect on motility and viability parameters of frozen-thawed stallion sperm. [ABSTRACT FROM AUTHOR]

Paraquat (PQ) poisoning often leads to severe lung injuries, in which the mitochondria damage plays a critical role. Mitoquinone (MitoQ), a newly designed mitochondria‐targeted antioxidant, has been proved for its benefit in mitochondria protection. However, the role of MitoQ in PQ‐induced lung injury remains unclear. Thus, this study was performed to investigate the effect of MitoQ on PQ‐induced lung injury and its underlying mechanisms. Our work showed that PQ caused the inhibition of A549 lung epithelial cell viability in a dose‐dependent manner, while MitoQ remarkably mitigated the PQ‐induced cell viability suppression. Besides this, PQ‐mediated apoptosis of A549 cells was significantly attenuated by MitoQ, as indicated by the TUNEL assay and mitochondria membrane potential assay. Moreover, the intracellular reactive oxygen species (ROS) production was also dramatically suppressed when cotreated MitoQ with PQ. This could be ascribed to enhanced mitochondrial fusion mediated by Mitofusin 1 (MFN1)/Mitofusin 2 (MFN2), because MitoQ preserved mitochondrial network integrity, as reflected by MitoTracker staining, and MitoQ also increased the expression of MFN1/MFN2 in A549 cells after PQ treatment. Our data suggested MitoQ mitigated PQ‐induced lung epithelial cell injury by promoting MFN1/MFN2‐mediated mitochondrial fusion, and MitoQ might be a potential candidate drug for the treatment of PQ‐induced lung injury. [ABSTRACT FROM AUTHOR]

Oxidative stress is associated with impaired sperm quality after thawing. Since mitochondria are the main source of reactive oxygen species (ROS) in sperm, the aim of this study was to investigate the effects of targeted mitochondrial antioxidant mitoquinone (MitoQ) and non-targeted mitochondrial antioxidant pentoxifylline (PTX) during cooling and cryopreservation of rooster sperm. Sperm samples were collected from 15 roosters aged 28 wk and diluted with Beltsville extender. After dilution and addition of treatments (50, 100, and 200 pMol MitoQ and 0.5, 0.75, and 1 μM PTX), samples were cooled for 2 h to 4°C and they were first analyzed at this stage and were frozen and re-evaluated after thawing. After the freezing and thawing, level of 100 pMol MitoQ significantly increased total motility (TM), progressive motility (PGM), curvilinear velocity (VCL), membrane integrity, viability, total antioxidant capacity (TAC) and the glutathione peroxidase (GPx), as well as the level of 50 pMol significantly increased TM, PGM, average path velocity (VAP), straight-line velocity (VSL), membrane integrity, viability, and mitochondrial activity. Moreover, these 2 levels (50 and 100 PMol) decreased malondialdehyde and sperm with abnormal morphology. Addition of 0.75 μM PTX also increased total motility compared to the control group and levels of 0.5 and 0.75 μM decreased sperm with abnormal morphology. It could be concluded the addition of MitoQ and PTX can be useful for sperm cryopreservation industry and reduce the harmful effects of freeze-thawing.

Inorganic arsenic is a well-established environmental toxicant linked to acute liver injury, fibrosis, and cancer. While oxidative stress, pyroptosis, and ferroptosis are known contributors, the role of PTEN-induced kinase 1 (PINK1)-mediated mitophagy in arsenic-induced hepatic immunotoxicity remains underexplored. Our study revealed that acute arsenic exposure prompts differentiation of hepatic dendritic cells (DCs) and T helper (Th) 1, Th2, Th17, and regulatory T (Treg) cells, alongside increased transcription factors and cytokines. Inorganic arsenic triggered liver redox imbalance, leading to elevated alanine transaminase (ALT), hydrogen peroxide (H 2 O 2), malondialdehyde (MDA), and activation of nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) pathway. PINK1-mediated mitophagy was initiated, and its inhibition exacerbates H 2 O 2 accumulation while promoting DCs/Th1/Th2/Treg differentiation in the liver of arsenic-exposed mice. Mitoquinone (MitoQ) pretreatment relieved arsenic-induced acute liver injury and immune imbalance by activating Nrf2/HO-1 and PINK1-mediated mitophagy. To our knowledge, this is the first report identifying PINK1-mediated mitophagy as a protective factor against inorganic arsenic-induced hepatic DCs/Th1/Th2 differentiation. This study has provided new insights on the immunotoxicity of inorganic arsenic and established a foundation for exploring preventive and therapeutic strategies targeting PINK1-mediated mitophagy in acute liver injury. Consequently, the application of mitochondrial antioxidant MitoQ may offer a promising treatment for the metalloid-induced acute liver injury. [Display omitted] • Arsenic induces hepatic DCs/Th1/Th2/Th17/Treg differentiation and redox imbalance. • Mitophagy mitigates arsenic-induced hepatic DCs/Th1/Th2/Treg differentiation. • MitoQ activated Nrf2/HO-1 pathway and PINK1-mediated mitophagy in liver. • MitoQ ameliorates arsenic-induced acute liver injury and immune disturbances. [ABSTRACT FROM AUTHOR]

Evidence exists to suggest that ROS induce muscular injury with a subsequent decrease in physical performance. Supplementation with certain antioxidants is important for physically active individuals to hasten recovery from fatigue and to prevent exercise damage. The use of nutritional supplements associated with exercise, with the aim of improving health, optimizing training or improving sports performance, is a scientific concern that not only drives many research projects but also generates great expectations in the field of their application in pathology. Since its discovery in the 1970s, coenzyme Q10 (CoQ10) has been one of the most controversial molecules. The interest in determining its true value as a bioenergetic supplement in muscle contraction, antioxidant or in the inflammatory process as a muscle protector in relation to exercise has been studied at different population levels of age, level of physical fitness or sporting aptitude, using different methodologies of effort and with the contribution of data corresponding to very diverse variables. Overall, in the papers reviewed, although the data are inconclusive, they suggest that CoQ10 supplementation may be an interesting molecule in health or disease in individuals without a pathological deficiency and when used for optimising exercise performance. Considering the results observed in the literature, and as a conclusion of this systematic review, we could say that it is an interesting molecule in sports performance. However, clear approaches should be considered when conducting future research. [ABSTRACT FROM AUTHOR]

Retinal ischemia–reperfusion injury (RIRI) is an important pathological process of many ocular diseases. Mitoquinone (MitoQ), a mitochondrial targeted antioxidant, is a potential compound for therapeutic development of RIRI. This study observed the effect of MitoQ on RIRI, and further explored its possible molecular mechanism. Temporary increase in intraocular pressure was used to establish rat model of RIRI to observe the effect of MitoQ treatment on retinal function, pathological injury, oxidative stress, inflammation and apoptosis. Immunohistochemistry and Western blot were used to detect expressions of cleaved caspase 3, B cell leukemia/lymphoma 2 associated X (Bax), nicotinamide adenine dinucleotide phosphate oxidase (NOX1), NOX4, cleaved‐Notch 1, hairy and enhancer of split 1 (Hes1), and sirtuin 1 (SIRT 1) in retina were detected by immunohistochemistry and Western blot. MitoQ treatment significantly improved retinal function and pathological injury, inhibited the over‐production of reactive oxygen species, increased the expression of superoxide dismutase 1 (SOD 1), suppressed the releases of inflammatory cytokines, and inhibited retinal cells apoptosis. MitoQ also down‐regulated the expressions of cleaved caspase 3, Bax, NOX 1, NOX 4, cleaved‐Notch 1, and Hes 1, increased the expression of SIRT 1 protein and its activity. These effects were significantly reversed by SIRT1 inhibitor EX527. Our data suggests that MitoQ, as a potentially effective drug for improving RIRI, may act through the SIRT1/Notch1/NADPH signal axis. [ABSTRACT FROM AUTHOR]

Extensive studies have reported that interaction of α-synuclein amyloid species with neurons is a crucial mechanistic characteristic of Parkinson's disease (PD) and small molecules can downregulate the neurotoxic effects induced by protein aggregation. However, the exact mechanism(s) of these neuroprotective effects by small molecules remain widely unknown. In the present study, α-synuclein samples in the amyloidogenic condition were aged for 120 h with or without different concentrations of mitoquinone (MitoQ) as a quinone derivative compound and the amyloid characteristics and the relevant neurotoxicity were evaluated by Thioflavin T (ThT)/Nile red fluorescence, Congo red absorption, circular dichroism (CD), transmission electron microscopy (TEM), cell viability, lactate dehydrogenase (LDH), reactive oxygen species (ROS), reactive nitrogen species (RNS), malondialdehyde (MDA), superoxide dismutase (SOD), and caspase-9/-3 activity assays. Results clearly showed the capacity of MitoQ on the inhibition of the formation of α-synuclein fibrillation products through modulation of the aggregation pathway by an effect on the kinetic parameters. Also, it was shown that α-synuclein samples aged for 120 h with MitoQ trigger less neurotoxic effects against SH-SY5Y cells than α-synuclein amyloid alone. Indeed, co-incubation of α-synuclein with MitoQ reduced the membrane leakage, oxidative and nitro-oxidative stress, modifications of macromolecules, and apoptosis. [ABSTRACT FROM AUTHOR]

Mitochondria control various processes in cellular metabolic homeostasis, such as adenosine triphosphate production, generation and clearance of reactive oxygen species, control of intracellular Ca2+ and apoptosis, and are thus a critical therapeutic target for metabolic syndrome (MetS). The mitochondrial targeted antioxidant mitoquinone (MitoQ) reduces mitochondrial oxidative stress, prevents impaired mitochondrial dynamics, and increases mitochondrial turnover by promoting autophagy (mitophagy) and mitochondrial biogenesis, which ultimately contribute to the attenuation of MetS conditions, including obesity, insulin resistance, hypertension and cardiovascular disease. The regulatory effect of MitoQ on mitochondrial homeostasis is mediated through AMPK and its downstream signaling pathways, including MTOR, SIRT1, Nrf2 and NF-κB. However, there are few reviews focusing on the critical role of MitoQ as a therapeutic agent in the treatment of MetS. The purpose of this review is to summarize the mitochondrial role in the pathogenesis of MetS, especially in obesity and type 2 diabetes, and discuss the effect and underlying mechanism of MitoQ on mitochondrial homeostasis in MetS. [ABSTRACT FROM AUTHOR]

Background: Primary osteoarthritis (OA) occurs without identifiable underlying causes such as previous injuries or specific medical conditions. Age is a major contributing factor to OA, and as one ages, various joint tissues undergo gradual change, including degeneration of the articular cartilage, alterations in subchondral bone (SCB) morphology, and inflammation of the synovium., Methods: We investigated the prevalence of primary OA in aged, genetically diverse UM-HET3 mice. Articular cartilage (AC) integrity and SCB morphology were assessed in 182 knee joints of 22-25 months old mice using the Osteoarthritis Research Society International (OARSI) scoring system and micro-CT, respectively. Additionally, we explored the effects of methylene blue (MB) and mitoquinone (MitoQ), two agents that affect mitochondrial function, on the prevalence and progression of OA during aging., Results: Aged UM-HET3 mice showed a high prevalence of primary OA in both sexes. Significant positive correlations were found between cumulative AC (cAC) scores and synovitis in both sexes, and osteophyte formation in female mice. Ectopic chondrogenesis did not show significant correlations with cAC scores. Significant direct correlations were found between AC scores and inflammatory markers in chondrocytes, including matrix metalloproteinase-13, inducible nitric oxide synthase, and the NLR family pyrin domain containing-3 inflammasome in both sexes, indicating a link between OA severity and inflammation. Additionally, markers of cell cycle arrest, such as p16 and β-galactosidase, also correlated with AC scores. In male mice, no significant correlations were found between SCB morphology traits and cAC scores, while in female mice, significant correlations were found between cAC scores and tibial SCB plate bone mineral density. Notably, MB and MitoQ treatments influenced the disease's progression in a sex-specific manner. MB treatment significantly reduced cAC scores at the medial knee joint, while MitoQ treatment reduced cAC scores, but these did not reach significance., Conclusions: Our study provides comprehensive insights into the prevalence and progression of primary OA in aged UM-HET3 mice, highlighting the sex-specific effects of MB and MitoQ treatments. The correlations between AC scores and various pathological factors underscore the multifaceted nature of OA and its association with inflammation and subchondral bone changes., (© 2024. The Author(s).)

Apoptotic cells may release specific metabolites to act as messengers during the apoptotic process. This study represents the first attempt to identify potential apoptotic metabolites in postmortem muscle. Ninety potential apoptotic metabolites in beef were selected and analyzed through targeted metabolomics, with 84 of them exhibiting significant differences over the postmortem time. Following the addition of the mitochondria-targeted antiapoptotic agent mitoquinone to postmortem muscle, metabolomic analysis revealed that 73 apoptotic metabolites still underwent significant changes, even against the backdrop of altered apoptosis. Of these 73 apoptotic metabolites, 54 exhibited similar trends at various treatment times with adding mitoquinone, including lipids (6), amino acids (27), nucleosides (11), and carbohydrate and energy metabolism (10). Mitoquinone significantly reduced the levels of most apoptotic metabolites, and inhibition of apoptosis resulted in a significant decrease in the levels of numerous apoptotic metabolites. Consequently, these apoptotic metabolites are considered complementary to apoptosis in postmortem muscle, with their increased levels potentially promoting apoptosis. Noteworthy apoptotic metabolites, such as glycerol 3-phosphate, serine, AMP, ATP, GMP, and creatine, were identified as active signaling molecules that attract and recruit phagocytes during apoptosis, assisting in recognizing apoptotic cells by phagocytes. This study provides, for the first time, insights into potential apoptotic metabolites in postmortem muscle, contributing to a better understanding of meat biochemistry.

Methylene blue (MB) is a well-established antioxidant that has been shown to improve mitochondrial function in both in vitro and in vivo settings. Mitoquinone (MitoQ) is a selective antioxidant that specifically targets mitochondria and effectively reduces the accumulation of reactive oxygen species. To investigate the effect of long-term administration of MB on skeletal morphology, we administered MB to aged (18 months old) female C57BL/J6 mice, as well as to adult male and female mice with a genetically diverse background (UM-HET3). Additionally, we used MitoQ as an alternative approach to target mitochondrial oxidative stress during aging in adult female and male UM-HET3 mice. Although we observed some beneficial effects of MB and MitoQ in vitro , the administration of these compounds in vivo did not alter the progression of age-induced bone loss. Specifically, treating 18-month-old female mice with MB for 6 or 12 months did not have an effect on age-related bone loss. Similarly, long-term treatment with MB from 7 to 22 months or with MitoQ from 4 to 22 months of age did not affect the morphology of cortical bone at the mid-diaphysis of the femur, trabecular bone at the distal-metaphysis of the femur, or trabecular bone at the lumbar vertebra-5 in UM-HET3 mice. Based on our findings, it appears that long-term treatment with MB or MitoQ alone, as a means to reduce skeletal oxidative stress, is insufficient to inhibit age-associated bone loss. This supports the notion that interventions solely with antioxidants may not provide adequate protection against skeletal aging.

Background: Fine particulate matter (PM 2.5 ), an important component of ambient air pollution, induces significant adverse health effects. MitoQuinone (MitoQ), a mitochondria-targeted antioxidant, has been reported to play a protective role in various diseases. However, the roles of MitoQ in PM 2.5 induced pulmonary toxicity remains to be elucidated., Methods: All the experiments were performed at Higher Educational Key Laboratory for Translational Oncology of Fujian Province, Putian City, China in 2023. Pulmonary epithelial cells (A549) were pretreated with 4 μM MitoQ for 2 h and exposed to PM 2.5 for 24 h. Cell viability was tested through CCK8 assay. Oxidative stress state and active mitochondria was used to study MitoQ's effect on PM 2.5 induced injury, and cell apoptosis was measured using a flow cytometer and analyzed by Bcl-2 family., Results: MitoQ pretreatment significantly relieved a decreased cell viability, subsequently, MitoQ alleviated ROS production and prevented the reduction of T-AOC and GSH and increased the expression of NF-E2-related factor 2 (Nrf2) and p62 in A549 cells exposed to PM 2.5 . MitoQ restored the decreased mitochondrial dysfunction and dynamics disorder and inhibited activated mitochondrial-mediated apoptosis induced by PM 2.5 . Furthermore, the decreased ratio of Bcl-2/Bax and expression of Mcl-1 and the enhanced expression of Caspase-3 were reversed by MitoQ pretreatment., Conclusion: MitoQ might be regarded as a potential drug to relieve PM 2.5 induced pulmonary epithelial cells damage., (Copyright© 2024 Weng et al. Published by Tehran University of Medical Sciences.)

Mitoquinone (MitoQ), a mitochondria-targeted antioxidant, has been used to treat several diseases. The present study aimed to investigate the therapeutic effects of MitoQ in benign prostatic hyperplasia (BPH) models and their underlying molecular mechanisms. In this study, we determined that MitoQ inhibited dihydrotestosterone (DHT)-induced cell proliferation and mitochondrial ROS by inhibiting androgen receptor (AR) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) signaling in prostate epithelial cells. Molecular modeling revealed that DHT may combine with AR and NLRP3, and that MitoQ inhibits both AR and NLRP3. AR and NLRP3 downregulation using siRNA showed the linkage among AR, NLRP3, and MitoQ. MitoQ administration alleviated pathological prostate enlargement and exerted anti-proliferative and antioxidant effects by suppressing the AR and NLRP3 signaling pathways in rats with BPH. Hence, our findings demonstrated that MitoQ is an inhibitor of NLPR3 and AR and a therapeutic agent for BPH treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Mitochondrial dysfunction is an essential part of the pathophysiology of asthma, and potential treatments that target the malfunctioning mitochondria have attracted widespread attention. We have previously demonstrated that aberrant epithelial β-catenin signaling played a crucial role in a toluene diisocyanate (TDI)-induced steroid-insensitive asthma model. The objective of this study was to determine if the mitochondrially targeted antioxidant mitoquinone(MitoQ) regulated the activation of β-catenin in TDI-induced asthma. Mice were sensitized and challenged with TDI to generate a steroid-insensitive asthma model. Human bronchial epithelial cells (16HBE) were exposed to TDI-human serum albumin (HSA) and ethidium bromide(EB) to simulate the TDI-induced asthma model and mitochondrial dysfunction. MitoQ dramatically attenuated TDI-induced AHR, airway inflammation, airway goblet cell metaplasia, and collagen deposition and markedly protected epithelial mitochondrial functions by preserving mass and diminishing the production of reactive oxygen species (ROS). MitoQ administration stabilized β‐catenin destruction complex from disintegration and inhibited the activation of β‐catenin. Similarly, YAP1, an important constituent of β‐catenin destruction complex, was inhibited by Dasatinib, which alleviated airway inflammation and the activation of β‐catenin, and restored mitochondrial mass. In vitro, treating 16HBE cells with EB led to the activation of YAP1 and β-catenin signaling, decreased the expression of glucocorticoid receptors and up-regulated interleukin (IL)-1β, IL6 and IL-8 expression. Our results indicated that mitochondria mediates airway inflammation by regulating the stability of the β-catenin destruction complex and MitoQ might be a promising therapeutic approach to improve airway inflammation and severe asthma. The data that support the findings of this study are available from the corresponding author upon reasonable request. Some data may not be made available because of privacy or ethical restrictions. [Display omitted] • Mitoquinone reduces airway inflammation in TDI-induced steroid-resistant asthma. • Mitoquinone stabilizes β-catenin destruction complex to alleviate TDI-induced asthma. • YAP/TAZ interacts with β-catenin signaling to mediate airway inflammation. • Mitochondrial dysfunction activates YAP1 and β-catenin signaling. [ABSTRACT FROM AUTHOR]

Mitochondrial oxidative stress has been a crucial mediator in acetaminophen (APAP)-induced hepatotoxicity. MitoQ, an analog of coenzyme Q10, is targeted towards mitochondria and acts as a potent antioxidant. This study aimed to explore the effect of MitoQ on APAP-induced liver injury and its possible mechanisms. To investigate this, CD-1 mice and AML-12 cells were treated with APAP. Hepatic MDA and 4-HNE, two markers of lipid peroxidation (LPO), were elevated as early as 2 h after APAP. Oxidized lipids were rapidly upregulated in APAP-exposed AML-12 cells. Hepatocyte death and mitochondrial ultrastructure alterations were observed in APAP-induced acute liver injury. The in vitro experiments showed that mitochondrial membrane potentials and OXPHOS subunits were downregulated in APAP-exposed hepatocytes. MtROS and oxidized lipids were elevated in APAP-exposed hepatocytes. We discovered that APAP-induced hepatocyte death and liver injury were ameliorated by attenuation of protein nitration and LPO in MitoQ-pretreated mice. Mechanistically, knockdown of GPX4, a key enzyme for LPO defense systems, exacerbated APAP-induced oxidized lipids, but did not influence the protective effect of MitoQ on APAP-induced LPO and hepatocyte death. Whereas knockdown of FSP1, another key enzyme for LPO defense systems, had little effect on APAP-induced lipid oxidation but partially weakened the protection of MitoQ on APAP-induced LPO and hepatocyte death. These results suggest that MitoQ may alleviate APAP-evoked hepatotoxicity by eliminating protein nitration and suppressing hepatic LPO. MitoQ prevents APAP-induced liver injury partially dependent of FSP1 and independent of GPX4. • LPO is implicated in APAP-induced acute liver injury. • MitoQ alleviates APAP hepatotoxicity by eliminating protein nitration and inhibiting LPO. • MitoQ prevents APAP-induced liver injury partially dependent of FSP1 and independent of GPX4. [ABSTRACT FROM AUTHOR]

• Acute BLM exposure induces ALI and pulmonary epithelial death. • Fer-1 protects against BLM-induced ALI and pulmonary epithelial death. • BLM stimulates mitochondrial ROS in bronchial epithelial cells. • Mitochondria-targeted antioxidant attenuates BLM-evoked mitochondrial ROS and lipid peroxidation. Numerous studies demonstrated that bleomycin (BLM) caused acute lung injury (ALI). This study explored the role of mitochondrial reactive oxygen species (ROS) on BLM-induced ALI and pulmonary epithelial ferroptosis. Male C57BL/6J mice were intratracheally injected with BLM (3.0 mg/kg). BEAS-2B cells, human bronchial epithelial cells, were cultured with BLM (10 μg/ml). Pulmonary MDA and 4-HNE, two markers of lipid peroxidation, were elevated in BLM-exposed mice. Oxidized lipids were upregulated in BLM-exposed BEAS-2B cells. Ferroptosis-characteristic ultrastructure, mainly disappearance of mitochondrial bilayer membrane structure and cristae, was observed in BLM-exposed pulmonary epithelium. Ferrostatin-1, a specific inhibitor of ferroptosis, attenuated BLM-evoked pulmonary lipid peroxidation, ferroptosis-characteristic mitochondrial ultrastructure and pulmonary epithelial death. The in vitro experiments showed that mitochondrial membrane potentials (MMPs) were decreased and mitochondrial ROS were increased in BLM-exposed BEAS-2B cells. Mitoquinone (MitoQ), a mitochondria-targeted antioxidant, prevented BLM-induced MMP reduction and mitochondrial ROS elevation in BEAS-2B cells. The in vivo experiment found that MitoQ attenuated BLM-evoked GSH depletion and lipid peroxidation in mouse lungs. Moreover, MitoQ prevented BLM-induced ferroptosis-characteristic mitochondrial changes, pulmonary epithelial death and ALI. In conclusion, mitochondrial ROS are an initiator of BLM-induced pulmonary epithelial ferroptosis. Mitochondria-targeted antioxidants may be used as potential therapeutic agents for BLM-induced ALI. [ABSTRACT FROM AUTHOR]

Mitochondria are the most important organelles and the main reactive oxygen species producers in spermatozoa. The objective of this study was to investigate the effects of mitochondria-targeted antioxidant mitoquinone (MitoQ) supplementation in boar semen extender during cryopreservation on sperm quality, antioxidant status and the changes of sperm mitochondrial proteomic profile. Semen collected from 10 Large White boars was cryopreserved in lactose-egg yolk extender supplemented with various concentrations of MitoQ (0, 5, 10, 20 and 40 μM). After thawing, sperm characteristics, antioxidant status and the abundance of hexose transporters (GLUT 3 and 8) were analyzed. The comprehensive mitochondrial proteomic profiling was performed on spermatozoa in the control and MitoQ 10 groups. Supplementation with 10 μM of MitoQ resulted in the highest post-thaw sperm motility and kinematics. Sperm quality, antioxidant capacity and glucose transporter abundance of frozen-thawed boar sperm were also elevated in the MitoQ 10 group. Excessive MitoQ (40 μM) supplementation induced a reduction of sperm motility parameters, sperm quality and antioxidant status and the abundance of GLUT3 and 8 proteins. A total of 189 proteins were defied as differentially expressed proteins (DEPs) using fold change (FC) > 1.2 with P < 0.05, and 33 of them were dramatically (FC > 1.5) regulated by MitoQ. These DEPs are mainly involved in sperm motility, energy metabolism and oxidative phosphorylation. Our data suggest that the beneficial effect of MitoQ on cryopreserved boar semen is achieved by regulating sperm antioxidant capacity and the mitochondrial proteins related to motility and metabolism. • MitoQ improves the sperm characteristics of cryopreserved boar semen. • MitoQ protects boar sperm against oxidative stress during cryopreservation. • MitoQ elevates the abundance of hexose transporters in frozen-thawed boar sperm. • Excessive MitoQ has detrimental effects on boar sperm during cryopreservation. • MitoQ changes the mitochondrial proteomic profile of cryopreserved boar sperm. [ABSTRACT FROM AUTHOR]

Cancer chemoprevention is an approach that offers huge potential for preventing/retarding carcinogenesis. MitoQ is well-known and extensively studied mitochondria-targeted antioxidants for its applications in diseases linked with oxidative stress. In the present study chemopreventive potential of mitoQ was studied with a focus on the role of gap-junctions and p53 at an advanced stage of HCC. BALB/c mice model of hepatocarcinogenesis was established using N-nitrosodiethylamine as a carcinogen (200 mg/kg b. w., cumulative dose, intraperitoneally). The chemopreventive effect of mitoQ was studied by pre-protecting animals with mitoQ (0.125 mg/kg b. w., orally once a week) till the termination of the study. The tumors developed in the course of the study were histopathologically analyzed and statistically evaluated. The mechanistic role of mitoQ was investigated in terms of mitochondrial oxidative stress, expression of 8-OHdG, Cx26, Cx32, p53 and status of gap-junctional intercellular communication (GJIC) in tumors. Chemopreventive activity of mitoQ was evident from improved survival of animals, significantly (p ≤ 0.05) lower tumor multiplicity, tumor incidence and a total number of tumors. MitoQ treatment significantly (p ≤ 0.05) decreased mitochondrial oxidative stress as indicated by reduced mtROS and mtLPO. Increased staining intensity of 8-OHdG and internalization of Cx26, Cx32 which was observed in hepatic tumors was reduced upon mitoQ treatment. Furthermore, the expression of Cx26, Cx32 and p53 was significantly increased along with improvement in GJIC in mitoQ treatment group. MitoQ demonstrated its chemopreventive potential probably by regulating mtROS, connexins and p53 in hepatocarcinogenesis. • MitoQ exhibited significant chemopreventive effect against hepatocellular carcinoma (HCC). • MitoQ attenuated mitochondrial oxidative stress and lipid peroxidation in hepatic tumors. • MitoQ significantly improved the expression of p53 in hepatic tumors. • MitoQ decreased the expression of Cx26, Cx32 and decreased their internalization in hepatic tumors. • MitoQ improved Gap Junction Intercellular Communication in hepatic tumors. [ABSTRACT FROM AUTHOR]

Oxidative stress is associated with impaired sperm quality after thawing. Since mitochondria are the main source of reactive oxygen species (ROS) in sperm, the aim of this study was to investigate the effects of targeted mitochondrial antioxidant mitoquinone (MitoQ) and non-targeted mitochondrial antioxidant pentoxifylline (PTX) during cooling and cryopreservation of rooster sperm. Sperm samples were collected from 15 roosters aged 28 wk and diluted with Beltsville extender. After dilution and addition of treatments (50, 100, and 200 pMol MitoQ and 0.5, 0.75, and 1 μM PTX), samples were cooled for 2 h to 4°C and they were first analyzed at this stage and were frozen and re-evaluated after thawing. After the freezing and thawing, level of 100 pMol MitoQ significantly increased total motility (TM), progressive motility (PGM), curvilinear velocity (VCL), membrane integrity, viability, total antioxidant capacity (TAC) and the glutathione peroxidase (GPx), as well as the level of 50 pMol significantly increased TM, PGM, average path velocity (VAP), straight-line velocity (VSL), membrane integrity, viability, and mitochondrial activity. Moreover, these 2 levels (50 and 100 PMol) decreased malondialdehyde and sperm with abnormal morphology. Addition of 0.75 μM PTX also increased total motility compared to the control group and levels of 0.5 and 0.75 μM decreased sperm with abnormal morphology. It could be concluded the addition of MitoQ and PTX can be useful for sperm cryopreservation industry and reduce the harmful effects of freeze-thawing. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a major cause of disability and death. Mild TBI (mTBI) constitutes ~75% of all TBI cases. Repeated exposure to mTBI (rmTBI), leads to the exacerbation of the symptoms compared to single mTBI. To date, there is no FDA-approved drug for TBI or rmTBI. This research aims to investigate possible rmTBI neurotherapy by targeting TBI pathology-related mechanisms. Oxidative stress is partly responsible for TBI/rmTBI neuropathologic outcomes. Thus, targeting oxidative stress may ameliorate TBI/rmTBI consequences. In this study, we hypothesized that mitoquinone (MitoQ), a mitochondria-targeted antioxidant, would ameliorate TBI/rmTBI associated pathologic features by mitigating rmTBI-induced oxidative stress. To model rmTBI, C57BL/6 mice were subjected to three concussive head injuries. MitoQ (5 mg/kg) was administered intraperitoneally to rmTBI+MitoQ mice twice per week over one month. Behavioral and cognitive outcomes were assessed, 30 days following the first head injury, using a battery of behavioral tests. Immunofluorescence was used to assess neuroinflammation and neuronal integrity. Also, qRT-PCR was used to evaluate the expression levels of antioxidant enzymes. Our findings indicated that MitoQ alleviated fine motor function and learning impairments caused by rmTBI. Mechanistically, MitoQ reduced astrocytosis, microgliosis, dendritic and axonal shearing, and increased the expression of antioxidant enzymes. MitoQ administration following rmTBI may represent an efficient approach to ameliorate rmTBI neurological and cellular outcomes with no observable side effects. • MitoQ alleviated fine motor function and learning impairments caused by rmTBI • MitoQ reduced neuroinflammation nen neurite shearing, and increased the expression of antioxidant enzymes • MitoQ may be tefficient to ameliorate rmTBIconsequences • MitoQ may pose its effect byaffecting mitochondrial complexes [ABSTRACT FROM AUTHOR]

Coxsackievirus B3 (CVB3) infection causes acute pancreatitis and myocarditis. However, its pathophysiological mechanism is unclear. Here, we investigated how lipid metabolism is associated with exacerbation of CVB3 pathology using high-fat diet (HFD)-induced obese mice. Mice were intraperitoneally inoculated with 1×10 6 pfu/mouse of CVB3 after being fed a control or HFD to induce obesity. Mice were treated with mitoquinone (MitoQ) to reduce the level of mitochondrial ROS (mtROS). In obese mice, lipotoxicity of white adipose tissue-induced inflammation caused increased replication of CVB3 and mortality. The coxsackievirus adenovirus receptor increased under obese conditions, facilitating CVB3 replication in vitro . However, lipid-treated cells with receptor-specific inhibitors did not reduce CVB3 replication. In addition, lipid treatment increased mitochondria-derived vesicle formation and the number of multivesicular bodies. Alternatively, we found that inhibition of lipid-induced mtROS decreased viral replication. Notably, HFD-fed mice were more susceptible to CVB3-induced mortality in association with increased levels of CVB3 replication in adipose tissue, which was ameliorated by administration of the mtROS inhibitor, MitoQ. These results suggest that mtROS inhibitors can be used as potential treatments for CVB3 infection., Competing Interests: Conflict of interest: The authors declare no potential conflicts of interest., (Copyright © 2022. The Korean Association of Immunologists.)