The Experts below are selected from a list of 1248 Experts worldwide ranked by ideXlab platform
Michael P Murphy - One of the best experts on this subject based on the ideXlab platform.
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Mitochondria-targeted therapeutics, MitoQ and BGP-15, reverse aging-associated meiotic spindle defects in mouse and human oocytes.
Human reproduction (Oxford England), 2020Co-Authors: Usama Al-zubaidi, Michael P Murphy, Deepak Adhikari, Ozgur Cinar, Qing-hua Zhang, Wai Shan Yuen, Luk Rombauts, Rebecca L Robker, John CarrollAbstract:Do mitochondria-targeted therapies reverse ageing- and oxidative stress-induced spindle defects in oocytes from mice and humans? Exposure to MitoQ or BGP-15 during IVM protected against spindle and chromosomal defects in mouse oocytes exposed to oxidative stress or derived from reproductively aged mice whilst MitoQ promoted nuclear maturation and protected against chromosomal misalignments in human oocytes. Spindle and chromosomal abnormalities in oocytes are more prevalent with maternal aging, increasing the risk of aneuploidy, miscarriage and genetic disorders such as Down's syndrome. The origin of compromised oocyte function may be founded in mitochondrial dysfunction and increased reactive oxygen species (ROS). Oocytes from young and old mice were treated with MitoQ and/or BGP-15 during IVM. To directly induce mitochondrial dysfunction, oocytes were treated with H2O2, and then treated the MitoQ and/or BGP-15. Immature human oocytes were cultured with or without MitoQ. Each experiment was repeated at least three times, and data were analyzed by unpaired-sample t-test or chi-square test. Immature germinal vesicle (GV) stage oocytes from 1-, 12- and 18-month-old mice were obtained from preovulatory ovarian follicles. Oocytes were treated with MitoQ and/or BGP-15 during IVM. GV-stage human oocytes were cultured with or without MitoQ. Mitochondrial membrane potential and mitochondrial ROS were measured by live-cell imaging. Meiotic spindle and chromosome alignments were visualized by immunofluorescent labeling of fixed oocytes and the 3-dimensional images were analyzed by Imaris. MitoQ or BGP-15 during IVM protects against spindle and chromosomal defects in oocytes exposed to oxidative stress and in oocytes from aged mice (P < 0.001). In human oocytes, the presence of MitoQ during IVM promoted nuclear maturation and had a similar positive effect in protecting against chromosomal misalignments (P < 0.001). Our study identifies two excellent candidates that may help to improve fertility in older women. However, these potential therapies must be tested for efficacy in clinical IVM systems, and undergo thorough examination of resultant offspring in preclinical models before utilization. Our results using in-vitro systems for oocyte maturation in both mouse and human provide proof of principle that mitochondrially targeted molecules such as MitoQ and BGP-15 may represent a novel therapeutic approach against maternal aging-related spindle and chromosomal abnormalities. The project was financially supported by the National Health and Medical Research Council and Australian Research Council, Australia. U.A.-Z. was supported by the Iraqi Higher Education and Scientific Research Ministry PhD scholarship and O.C. was supported by TUBITAK-1059B191601275. M.P.M. consults for MitoQ Inc. and holds patents in mitochondria-targeted therapies. R.L.R. is an inventor on patents relating to the use of BGP-15 to improve gamete quality. N/A. © The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.
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Therapeutic potential of the mitochondria-targeted antioxidant MitoQ in mitochondrial-ROS induced sensorineural hearing loss caused by Idh2 deficiency
Elsevier, 2019Co-Authors: Ye-ri Kim, Jeong-in Baek, Sung Hwan Kim, Min-a Kim, Byeonghyeon Lee, Nari Ryu, Kyung-hee Kim, Deok-gyun Choi, Hye-min Kim, Michael P MurphyAbstract:Mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) is a major NADPH-producing enzyme which is essential for maintaining the mitochondrial redox balance in cells. We sought to determine whether IDH2 deficiency induces mitochondrial dysfunction and modulates auditory function, and investigated the protective potential of an antioxidant agent against reactive oxygen species (ROS)-induced cochlear damage in Idh2 knockout (Idh2−/−) mice. Idh2 deficiency leads to damages to hair cells and spiral ganglion neurons (SGNs) in the cochlea and ultimately to apoptotic cell death and progressive sensorineural hearing loss in Idh2−/− mice. Loss of IDH2 activity led to decreased levels of NADPH and glutathione causing abnormal ROS accumulation and oxidative damage, which might trigger apoptosis signal in hair cells and SGNs in Idh2−/− mice. We performed ex vivo experiments to determine whether administration of mitochondria-targeted antioxidants might protect or induce recovery of cells from ROS-induced apoptosis in Idh2-deficient mouse cochlea. MitoQ almost completely neutralized the H2O2-induced ototoxicity, as the survival rate of Idh2−/− hair cells were restored to normal levels. In addition, the lack of IDH2 led to the accumulation of mitochondrial ROS and the depolarization of ΔΨm, resulting in hair cell loss. In the present study, we identified that IDH2 is indispensable for the functional maintenance and survival of hair cells and SGNs. Moreover, the hair cell degeneration caused by IDH2 deficiency can be prevented by MitoQ, which suggests that Idh2−/− mice could be a valuable animal model for evaluating the therapeutic effects of various antioxidant candidates to overcome ROS-induced hearing loss. Keywords: Idh2, NADP+, ROS, Hearing loss, Antioxidant, Mito
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the mitochondria targeted antioxidant MitoQ modulates mitochondrial function and endoplasmic reticulum stress in pancreatic β cells exposed to hyperglycaemia
Cellular Physiology and Biochemistry, 2019Co-Authors: Irene Escribanolopez, Francesca Iannantuoni, Celia Banuls, Antonio Hernandezmijares, Noelia Diazmorales, Susana Rovirallopis, Milagros Rocha, Ramon Gomis, Michael P Murphy, Victor M VictorAbstract:Background/aims Mitochondria-targeted antioxidants such as MitoQuinone (MitoQ) have demonstrated protective effects against oxidative damage in several diseases. The increase in reactive oxygen species (ROS) production during glucose metabolism in β cells can be exacerbated under hyperglycaemic conditions such as type 2 diabetes (T2D), thus contributing to β cell function impairment. In the present work, we aimed to evaluate the effect of MitoQ on insulin secretion, oxidative stress, endoplasmic reticulum (ER) stress and nuclear factor kappa B (NFκB) signalling in a pancreatic β cell line under normoglycaemic (NG, 11.1 mM glucose), hyperglycaemic (HG, 25 mM glucose) and lipidic (palmitic acid (PA), 0.5mM) conditions. Methods We incubated the pancreatic β cell line INS-1E with or without MitoQ (0.5µM) under NG, HG and PA conditions. We then assessed the following parameters: glucose-induced insulin secretion, O₂ consumption (with a Clark-type electrode); mitochondrial function, oxidative stress parameters and calcium levels (by fluorescence microscopy); ER stress markers and NFκB-p65 protein levels (by western blotting). Results MitoQ increased insulin secretion and prevented the enhancement of ROS production and O₂ consumption and decrease in GSH levels that are characteristic under HG conditions. MitoQ also reduced protein levels of ER stress markers (GRP78 and P-eIF2α) and the proinflammatory nuclear transcription factor NFκB-p65, both of which increased under HG. MitoQ did not significantly alter ER stress markers under lipidic conditions. Conclusion Our findings suggest that treatment with MitoQ modulates mitochondrial function, which in turn ameliorates endoplasmic reticulum stress and NFκB activation, thereby representing potential benefits for pancreatic β cell function.
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MitoQ protects dopaminergic neurons in a 6 ohda induced pd model by enhancing mfn2 dependent mitochondrial fusion via activation of pgc 1α
Biochimica et Biophysica Acta, 2018Co-Authors: Ye Xi, Dayun Feng, Ronglin Wang, Michael P Murphy, Qian Yang, Gang ZhaoAbstract:Abstract Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra compacta (SNc). Although mitochondrial dysfunction is the critical factor in the pathogenesis of PD, the underlying molecular mechanisms are not well understood, and as a result, effective medical interventions are lacking. Mitochondrial fission and fusion play important roles in the maintenance of mitochondrial function and cell viability. Here, we investigated the effects of MitoQ, a mitochondria-targeted antioxidant, in 6-hydroxydopamine (6-OHDA)-induced in vitro and in vivo PD models. We observed that 6-OHDA enhanced mitochondrial fission by decreasing the expression of Mfn1, Mfn2 and OPA1 as well as by increasing the expression of Drp1 in the dopaminergic (DA) cell line SN4741. Notably, MitoQ treatment particularly upregulated the Mfn2 protein and mRNA levels and promoted mitochondrial fusion in the presence of 6-OHDA in a Mfn2-dependent manner. In addition, MitoQ also stabilized mitochondrial morphology and function in the presence of 6-OHDA, which further suppressed the formation of reactive oxygen species (ROS), as well as ameliorated mitochondrial fragmentation and cellular apoptosis. Moreover, the activation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) was attributed to the upregulation of Mfn2 induced by MitoQ. Consistent with these findings, administration of MitoQ in 6-OHDA-treated mice significantly rescued the decrease of Mfn2 expression and the loss of DA neurons in the SNc. Taken together, our findings suggest that MitoQ protects DA neurons in a 6-OHDA induced PD model by activating PGC-1α to enhance Mfn2-dependent mitochondrial fusion.
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i10 effects of MitoQ on behavioural and biochemical phenotypes of a huntington s disease mouse model
Journal of Neurology Neurosurgery and Psychiatry, 2018Co-Authors: Brigida R Pinho, Ana I Duarte, Liliana M Almeida, Paula M Canas, Paula I. Moreira, Michael P Murphy, Jorge M A OliveiraAbstract:Background Huntington’s disease (HD) is caused by mutant huntingtin (mHtt) and presents increased oxidative stress biomarkers, suggesting that aberrant redox signaling is associated with HD pathogenesis. Treatment with MitoQ, a mitochondria-targeted antioxidant, was neuroprotective in other models of neurodegenerative disorders, including ALS, Parkinson’s and Alzheimer’s diseases. Aims Evaluate the efficacy of MitoQ in rescuing HD phenotypes in vivo. Methods MitoQ (500 µM) or vehicle were administered in drinking water to wild-type and R6/2 HD mice (that expresses mHtt exon 1) from 5 weeks. Animal welfare and weight were monitored 2x/week and behaviour assessed at 5–6 and 10–11 weeks. Animals were euthanized at 11 weeks and tissues collected for MitoQ quantification by LC-MS/MS and protein analysis by Western-Blot. Results MitoQ was detected in brain, heart, liver and muscle. R6/2 mice differed from wild-type by presenting paw clasping, reduced body weight gain, decreased grasping strength, open-field rearings, and latency to fall from an accelerating rotarod. In the pole test, R6/2 mice required more time to descend a vertical pole than controls, and MitoQ rescued this phenotype. The R6/2 mouse cortex presented increased levels of NMDAR1 and inducible Hsp70, and decreased levels of TFAM, mGLUR2, Hsp40 and mitochondrial Hsp70. The R6/2 mouse liver presented decreased NRF2 and increased SOD2 and protein carbonyls. Treatment with MitoQ reduced NMDAR1 levels in the R6/2 mouse cortex. Conclusions: These results in the accelerated HD R6/2 mouse model suggest that MitoQ has some protective potential (fine motor tasks – pole test), possibly by attenuating excitotoxicity (NMDAR1). Further studies with a slower, more progressive HD model, expressing full-length mHtt, should help clarify the protective potential of MitoQ. Acknowledgements: FCT: P2020-PTDC/NEU-NMC/0412/2014; POCI-01-0145-FEDER-016577; 3599-PPCDT; UID/QUI/50006/2013; SFRH/BPD/102259/2014.
Antonio Hernandezmijares - One of the best experts on this subject based on the ideXlab platform.
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the mitochondria targeted antioxidant MitoQ modulates mitochondrial function and endoplasmic reticulum stress in pancreatic β cells exposed to hyperglycaemia
Cellular Physiology and Biochemistry, 2019Co-Authors: Irene Escribanolopez, Francesca Iannantuoni, Celia Banuls, Antonio Hernandezmijares, Noelia Diazmorales, Susana Rovirallopis, Milagros Rocha, Ramon Gomis, Michael P Murphy, Victor M VictorAbstract:Background/aims Mitochondria-targeted antioxidants such as MitoQuinone (MitoQ) have demonstrated protective effects against oxidative damage in several diseases. The increase in reactive oxygen species (ROS) production during glucose metabolism in β cells can be exacerbated under hyperglycaemic conditions such as type 2 diabetes (T2D), thus contributing to β cell function impairment. In the present work, we aimed to evaluate the effect of MitoQ on insulin secretion, oxidative stress, endoplasmic reticulum (ER) stress and nuclear factor kappa B (NFκB) signalling in a pancreatic β cell line under normoglycaemic (NG, 11.1 mM glucose), hyperglycaemic (HG, 25 mM glucose) and lipidic (palmitic acid (PA), 0.5mM) conditions. Methods We incubated the pancreatic β cell line INS-1E with or without MitoQ (0.5µM) under NG, HG and PA conditions. We then assessed the following parameters: glucose-induced insulin secretion, O₂ consumption (with a Clark-type electrode); mitochondrial function, oxidative stress parameters and calcium levels (by fluorescence microscopy); ER stress markers and NFκB-p65 protein levels (by western blotting). Results MitoQ increased insulin secretion and prevented the enhancement of ROS production and O₂ consumption and decrease in GSH levels that are characteristic under HG conditions. MitoQ also reduced protein levels of ER stress markers (GRP78 and P-eIF2α) and the proinflammatory nuclear transcription factor NFκB-p65, both of which increased under HG. MitoQ did not significantly alter ER stress markers under lipidic conditions. Conclusion Our findings suggest that treatment with MitoQ modulates mitochondrial function, which in turn ameliorates endoplasmic reticulum stress and NFκB activation, thereby representing potential benefits for pancreatic β cell function.
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the mitochondrial antioxidant MitoQ alleviates oxidative stress endoplasmic reticulum stress and mitochondrial function in pancreatic β cells under hyperglycaemic conditions
Free Radical Biology and Medicine, 2018Co-Authors: Irene Escribanolopez, Noelia Dazmorales, Aranzazu M De Maranon, Francesca Iannantuoni, Sandra Lopezdomenech, Zaida Abadjimenez, Rosa Falcontapiador, Vicente Mora, Celia Banuls, Antonio HernandezmijaresAbstract:MitoQ can exhibit protective effects against oxidative damage. The increase in ROS production during glucose metabolism in β cells is exacerbated under hyperglycaemic conditions such as type 2 diabetes (T2D), thus constituting a key contributor to β cell function impairment. Our aim was to evaluate the effect of MitoQ on oxidative stress, endoplasmic reticulum (ER) stress and NFκB signalling in a pancreatic β cell line under normoglycaemia (NG, 11.1 mM) and hyperglycaemia (HG, 25 mM). We employed the β cell line INS-1E treated with or without MitoQ (0.5 µM) under NG or HG conditions and assessed the following parameters: O2 consumption, mitochondrial function, oxidative stress, calcium, ER stress markers and NFκB-p65. MitoQ prevented the enhanced ROS production and O2 consumption and reduced GSH levels normally present under HG. MitoQ decreased ER stress markers (GRP78 and P-eif2α) and NFκB-p65, both of which increased under HG. These findings suggest that MitoQ treatment modulates oxidative stress and mitochondrial function, thereby ameliorating ER stress and NFκB activation. In this way, it possesses potential benefits as a treatment for insulin resistance-related diseases such as T2D.
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the mitochondria targeted antioxidant MitoQ modulates oxidative stress inflammation and leukocyte endothelium interactions in leukocytes isolated from type 2 diabetic patients
Redox biology, 2016Co-Authors: Irene Escribanolopez, Aranzazu M De Maranon, Celia Banuls, Noelia Diazmorales, Susana Rovirallopis, Samuel Orden, Angeles Alvarez, Milagros Rocha, Michael P Murphy, Antonio HernandezmijaresAbstract:It is not known if the mitochondria-targeted antioxidants such as MitoQuinone (MitoQ) can modulate oxidative stress and leukocyte-endothelium interactions in T2D patients. We aimed to evaluate the beneficial effect of MitoQ on oxidative stress parameters and leukocyte-endothelium interactions in leukocytes of T2D patients. The study population consisted of 98 T2D patients and 71 control subjects. We assessed metabolic and anthropometric parameters, mitochondrial reactive oxygen species (ROS) production, glutathione peroxidase 1 (GPX-1), NFκB-p65, TNFα and leukocyte-endothelium interactions. Diabetic patients exhibited higher weight, BMI, waist circumference, SBP, DBP, glucose, insulin, HOMA-IR, HbA1c, triglycerides, hs-CRP and lower HDL-c with respect to controls. Mitochondrial ROS production was enhanced in T2D patients and decreased by MitoQ. The antioxidant also increased GPX-1 levels and PMN rolling velocity and decreased PMN rolling flux and PMN adhesion in T2D patients. NFκB-p65 and TNFα were augmented in T2D and were both reduced by MitoQ treatment. Our findings support that the antioxidant MitoQ has an anti-inflammatory and antioxidant action in the leukocytes of T2D patients by decreasing ROS production, leukocyte-endothelium interactions and TNFα through the action of NFκB. These data suggest that mitochondria-targeted antioxidants such as MitoQ should be investigated as a novel means of preventing cardiovascular events in T2D patients.
Irene Escribanolopez - One of the best experts on this subject based on the ideXlab platform.
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the mitochondria targeted antioxidant MitoQ modulates mitochondrial function and endoplasmic reticulum stress in pancreatic β cells exposed to hyperglycaemia
Cellular Physiology and Biochemistry, 2019Co-Authors: Irene Escribanolopez, Francesca Iannantuoni, Celia Banuls, Antonio Hernandezmijares, Noelia Diazmorales, Susana Rovirallopis, Milagros Rocha, Ramon Gomis, Michael P Murphy, Victor M VictorAbstract:Background/aims Mitochondria-targeted antioxidants such as MitoQuinone (MitoQ) have demonstrated protective effects against oxidative damage in several diseases. The increase in reactive oxygen species (ROS) production during glucose metabolism in β cells can be exacerbated under hyperglycaemic conditions such as type 2 diabetes (T2D), thus contributing to β cell function impairment. In the present work, we aimed to evaluate the effect of MitoQ on insulin secretion, oxidative stress, endoplasmic reticulum (ER) stress and nuclear factor kappa B (NFκB) signalling in a pancreatic β cell line under normoglycaemic (NG, 11.1 mM glucose), hyperglycaemic (HG, 25 mM glucose) and lipidic (palmitic acid (PA), 0.5mM) conditions. Methods We incubated the pancreatic β cell line INS-1E with or without MitoQ (0.5µM) under NG, HG and PA conditions. We then assessed the following parameters: glucose-induced insulin secretion, O₂ consumption (with a Clark-type electrode); mitochondrial function, oxidative stress parameters and calcium levels (by fluorescence microscopy); ER stress markers and NFκB-p65 protein levels (by western blotting). Results MitoQ increased insulin secretion and prevented the enhancement of ROS production and O₂ consumption and decrease in GSH levels that are characteristic under HG conditions. MitoQ also reduced protein levels of ER stress markers (GRP78 and P-eIF2α) and the proinflammatory nuclear transcription factor NFκB-p65, both of which increased under HG. MitoQ did not significantly alter ER stress markers under lipidic conditions. Conclusion Our findings suggest that treatment with MitoQ modulates mitochondrial function, which in turn ameliorates endoplasmic reticulum stress and NFκB activation, thereby representing potential benefits for pancreatic β cell function.
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the mitochondrial antioxidant MitoQ alleviates oxidative stress endoplasmic reticulum stress and mitochondrial function in pancreatic β cells under hyperglycaemic conditions
Free Radical Biology and Medicine, 2018Co-Authors: Irene Escribanolopez, Noelia Dazmorales, Aranzazu M De Maranon, Francesca Iannantuoni, Sandra Lopezdomenech, Zaida Abadjimenez, Rosa Falcontapiador, Vicente Mora, Celia Banuls, Antonio HernandezmijaresAbstract:MitoQ can exhibit protective effects against oxidative damage. The increase in ROS production during glucose metabolism in β cells is exacerbated under hyperglycaemic conditions such as type 2 diabetes (T2D), thus constituting a key contributor to β cell function impairment. Our aim was to evaluate the effect of MitoQ on oxidative stress, endoplasmic reticulum (ER) stress and NFκB signalling in a pancreatic β cell line under normoglycaemia (NG, 11.1 mM) and hyperglycaemia (HG, 25 mM). We employed the β cell line INS-1E treated with or without MitoQ (0.5 µM) under NG or HG conditions and assessed the following parameters: O2 consumption, mitochondrial function, oxidative stress, calcium, ER stress markers and NFκB-p65. MitoQ prevented the enhanced ROS production and O2 consumption and reduced GSH levels normally present under HG. MitoQ decreased ER stress markers (GRP78 and P-eif2α) and NFκB-p65, both of which increased under HG. These findings suggest that MitoQ treatment modulates oxidative stress and mitochondrial function, thereby ameliorating ER stress and NFκB activation. In this way, it possesses potential benefits as a treatment for insulin resistance-related diseases such as T2D.
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the mitochondria targeted antioxidant MitoQ modulates oxidative stress inflammation and leukocyte endothelium interactions in leukocytes isolated from type 2 diabetic patients
Redox biology, 2016Co-Authors: Irene Escribanolopez, Aranzazu M De Maranon, Celia Banuls, Noelia Diazmorales, Susana Rovirallopis, Samuel Orden, Angeles Alvarez, Milagros Rocha, Michael P Murphy, Antonio HernandezmijaresAbstract:It is not known if the mitochondria-targeted antioxidants such as MitoQuinone (MitoQ) can modulate oxidative stress and leukocyte-endothelium interactions in T2D patients. We aimed to evaluate the beneficial effect of MitoQ on oxidative stress parameters and leukocyte-endothelium interactions in leukocytes of T2D patients. The study population consisted of 98 T2D patients and 71 control subjects. We assessed metabolic and anthropometric parameters, mitochondrial reactive oxygen species (ROS) production, glutathione peroxidase 1 (GPX-1), NFκB-p65, TNFα and leukocyte-endothelium interactions. Diabetic patients exhibited higher weight, BMI, waist circumference, SBP, DBP, glucose, insulin, HOMA-IR, HbA1c, triglycerides, hs-CRP and lower HDL-c with respect to controls. Mitochondrial ROS production was enhanced in T2D patients and decreased by MitoQ. The antioxidant also increased GPX-1 levels and PMN rolling velocity and decreased PMN rolling flux and PMN adhesion in T2D patients. NFκB-p65 and TNFα were augmented in T2D and were both reduced by MitoQ treatment. Our findings support that the antioxidant MitoQ has an anti-inflammatory and antioxidant action in the leukocytes of T2D patients by decreasing ROS production, leukocyte-endothelium interactions and TNFα through the action of NFκB. These data suggest that mitochondria-targeted antioxidants such as MitoQ should be investigated as a novel means of preventing cardiovascular events in T2D patients.
Robin A. J. Smith - One of the best experts on this subject based on the ideXlab platform.
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a double blind placebo controlled study to assess the mitochondria targeted antioxidant MitoQ as a disease modifying therapy in parkinson s disease
Movement Disorders, 2010Co-Authors: B J Snow, Robin A. J. Smith, Fiona L Rolfe, Michelle M Lockhart, C M Frampton, John D Osullivan, Michael P Murphy, Victor S C Fung, Kenneth Martin TaylorAbstract:Multiple lines of evidence point to mitochondrial oxidative stress as a potential pathogenic cause for Parkinson's disease (PD). MitoQ is a powerful mitochondrial antioxidant. It is absorbed orally and concentrates within mitochondria where it has been shown to protect against oxidative damage. We enrolled 128 newly diagnosed untreated patients with PD in a double-blind study of two doses of MitoQ compared with placebo to explore the hypothesis that, over 12 months, MitoQ would slow the progression of PD as measured by clinical scores, particularly the Unified Parkinson Disease Rating Scale. We showed no difference between MitoQ and placebo on any measure of PD progression. MitoQ does not slow the progression of PD, and this finding should be taken into account when considering the oxidative stress hypothesis for the pathogenesis of PD. © 2010 Movement Disorder Society
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animal and human studies with the mitochondria targeted antioxidant MitoQ
Annals of the New York Academy of Sciences, 2010Co-Authors: Robin A. J. Smith, Michael P MurphyAbstract:As mitochondrial oxidative damage contributes to a wide range of human diseases, antioxidants designed to be accumulated by mitochondria in vivo have been developed. The most extensively studied of these mitochondria-targeted antioxidants is MitoQ, which contains the antioxidant quinone moiety covalently attached to a lipophilic triphenylphosphonium cation. MitoQ has now been used in a range of in vivo studies in rats and mice and in two phase II human trials. Here, we review what has been learned from these animal and human studies with MitoQ.
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A double‐blind, placebo‐controlled study to assess the mitochondria‐targeted antioxidant MitoQ as a disease‐modifying therapy in Parkinson's disease
Movement Disorders, 2010Co-Authors: B J Snow, Robin A. J. Smith, Fiona L Rolfe, Michelle M Lockhart, C M Frampton, John D. O'sullivan, Michael P Murphy, Victor S C Fung, Kenneth Martin TaylorAbstract:Multiple lines of evidence point to mitochondrial oxidative stress as a potential pathogenic cause for Parkinson's disease (PD). MitoQ is a powerful mitochondrial antioxidant. It is absorbed orally and concentrates within mitochondria where it has been shown to protect against oxidative damage. We enrolled 128 newly diagnosed untreated patients with PD in a double-blind study of two doses of MitoQ compared with placebo to explore the hypothesis that, over 12 months, MitoQ would slow the progression of PD as measured by clinical scores, particularly the Unified Parkinson Disease Rating Scale. We showed no difference between MitoQ and placebo on any measure of PD progression. MitoQ does not slow the progression of PD, and this finding should be taken into account when considering the oxidative stress hypothesis for the pathogenesis of PD. © 2010 Movement Disorder Society
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Mitochondria-Targeted Antioxidant MitoQ10 Improves Endothelial Function and Attenuates Cardiac Hypertrophy
Hypertension, 2009Co-Authors: Delyth Graham, Robin A. J. Smith, N. N. Huynh, Carlene A. Hamilton, Elisabeth Beattie, Helena M. Cochemé, Michael P Murphy, Anna F. DominiczakAbstract:Mitochondria are a major site of reactive oxygen species production, which may contribute to the development of cardiovascular disease. Protecting mitochondria from oxidative damage should be an effective therapeutic strategy; however, conventional antioxidants are ineffective, because they cannot penetrate the mitochondria. This study investigated the role of mitochondrial oxidative stress during development of hypertension in the stroke-prone spontaneously hypertensive rat, using the mitochondria-targeted antioxidant, MitoQ(10). Eight-week-old male stroke-prone spontaneously hypertensive rats were treated with MitoQ(10) (500 mumol/L; n=16), control compound decyltriphenylphosphonium (decylTPP; 500 mumol/L; n=8), or vehicle (n=9) in drinking water for 8 weeks. Systolic blood pressure was significantly reduced by approximately 25 mm Hg over the 8-week MitoQ(10) treatment period compared with decylTPP (F=5.94; P=0.029) or untreated controls (F=65.6; P=0.0001). MitoQ(10) treatment significantly improved thoracic aorta NO bioavailability (1.16+/-0.03 g/g; P=0.002, area under the curve) compared with both untreated controls (0.68+/-0.02 g/g) and decylTPP-treated rats (0.60+/-0.06 g/g). Cardiac hypertrophy was significantly reduced by MitoQ(10) treatment compared with untreated control and decylTPP treatment (MitoQ(10): 4.01+/-0.05 mg/g; control: 4.42+/-0.11 mg/g; and decylTPP: 4.40+/-0.09 mg/g; ANOVA P=0.002). Total MitoQ(10) content was measured in liver, heart, carotid artery, and kidney harvested from MitoQ(10)-treated rats by liquid chromatography-tandem mass spectrometry. All of the organs analyzed demonstrated detectable levels of MitoQ(10), with comparable accumulation in vascular and cardiac tissues. Administration of the mitochondria-targeted antioxidant MitoQ(10) protects against the development of hypertension, improves endothelial function, and reduces cardiac hypertrophy in young stroke-prone spontaneously hypertensive rats. MitoQ(10) provides a novel approach to attenuate mitochondrial-specific oxidative damage with the potential to become a new therapeutic intervention in human cardiovascular disease.
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Fine-tuning the hydrophobicity of a mitochondria-targeted antioxidant.
FEBS Letters, 2004Co-Authors: Jordi Asin-cayuela, Abdul-rahman B. Manas, Andrew M. James, Robin A. J. Smith, Michael P MurphyAbstract:The mitochondria-targeted antioxidant MitoQ comprises a ubiquinol moiety covalently attached through an aliphatic carbon chain to the lipophilic triphenylphosphonium cation. This cation drives the membrane potential-dependent accumulation of MitoQ into mitochondria, enabling the ubiquinol antioxidant to prevent mitochondrial oxidative damage far more effectively than untargeted antioxidants. We sought to fine-tune the hydrophobicity of MitoQ so as to control the extent of its membrane binding and penetration into the phospholipid bilayer, and thereby regulate its partitioning between the membrane and aqueous phases within mitochondria and cells. To do this, MitoQ variants with 3, 5, 10 and 15 carbon aliphatic chains were synthesised. These molecules had a wide range of hydrophobicities with octan-1-ol/phosphate buffered saline partition coefficients from 2.8 to 20 000. All MitoQ variants were accumulated into mitochondria driven by the membrane potential, but their binding to phospholipid bilayers varied from negligible for MitoQ3 to essentially total for MitoQ15. Despite the span of hydrophobicites, all MitoQ variants were effective antioxidants. Therefore, it is possible to fine-tune the degree of membrane association of MitoQ and other mitochondria targeted compounds, without losing antioxidant efficacy. This indicates how the uptake and distribution of mitochondria-targeted compounds within mitochondria and cells can be controlled, thereby facilitating investigations of mitochondrial oxidative damage.
Chengyuan Tang - One of the best experts on this subject based on the ideXlab platform.
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Reactive oxygen species promote tubular injury in diabetic nephropathy: The role of the mitochondrial ros-txnip-nlrp3 biological axis
Elsevier, 2018Co-Authors: Yachun Han, Chengyuan Tang, Peng Gao, Xianghui Chen, Xiaofen Xiong, Ming Yang, Shikun Yang, Xuejing Zhu, Shuguang YuanAbstract:NLRP3/IL-1β activation via thioredoxin (TRX)/thioredoxin-interacting protein (TXNIP) following mitochondria ROS (mtROS) overproduction plays a key role in inflammation. However, the involvement of this process in tubular damage in the kidneys of patients with diabetic nephropathy (DN) is unclear. Here, we demonstrated that mtROS overproduction is accompanied by decreases in TRX expression and TXNIP up-regulation. In addition, we discovered that mtROS overproduction is also associated with increases in NLRP3/IL-1β and TGF-β expression in the kidneys of patients with DN and db/db mice. We reversed these changes in db/db mice by administering a peritoneal injection of MitoQ, an antioxidant targeting mtROS. Similar results were observed in human tubular HK-2 cells subjected to high-glucose (HG) conditions and treated with MitoQ. Treating HK-2 cells with MitoQ suppressed the dissociation of TRX from TXNIP and subsequently blocked the interaction between TXNIP and NLRP3, leading to the inhibition of NLRP3 inflammasome activation and IL-1β maturation. The effects of MitoQ were enhanced by pretreatment with TXNIP siRNA and abolished by pretreatment with monosodium urate (MSU) and TRX siRNA in vitro. These results suggest that mitochondrial ROS-TXNIP/NLRP3/IL-1β axis activation is responsible for tubular oxidative injury, which can be ameliorated by MitoQ via the inhibition of mtROS overproduction. Keywords: Diabetic nephropathy, Mitochondria, Reactive oxygen species (ROS), TRX/TXNIP, NLRP3 inflammasome, Mito
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the mitochondria targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via nrf2 pink1
Redox biology, 2017Co-Authors: Li Xiao, Xiaoxuan Xu, Chengyuan Tang, Liyu He, Dan Tang, Yan Xu, Jiahui Wang, Ming Wang, Fan Zhang, Anna GrekaAbstract:Mitochondria play a crucial role in tubular injury in diabetic kidney disease (DKD). MitoQ is a mitochondria-targeted antioxidant that exerts protective effects in diabetic mice, but the mechanism underlying these effects is not clear. We demonstrated that mitochondrial abnormalities, such as defective mitophagy, mitochondrial reactive oxygen species (ROS) overexpression and mitochondrial fragmentation, occurred in the tubular cells of db/db mice, accompanied by reduced PINK and Parkin expression and increased apoptosis. These changes were partially reversed following an intraperitoneal injection of MitoQ. High glucose (HG) also induces deficient mitophagy, mitochondrial dysfunction and apoptosis in HK-2 cells, changes that were reversed by MitoQ. Moreover, MitoQ restored the expression, activity and translocation of HG-induced NF-E2-related factor 2 (Nrf2) and inhibited the expression of Kelch-like ECH-associated protein (Keap1), as well as the interaction between Nrf2 and Keap1. The reduced PINK and Parkin expression noted in HK-2 cells subjected to HG exposure was partially restored by MitoQ. This effect was abolished by Nrf2 siRNA and augmented by Keap1 siRNA. Transfection with Nrf2 siRNA or PINK siRNA in HK-2 cells exposed to HG conditions partially blocked the effects of MitoQ on mitophagy and tubular damage. These results suggest that MitoQ exerts beneficial effects on tubular injury in DKD via mitophagy and that mitochondrial quality control is mediated by Nrf2/PINK.
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The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1
Redox biology, 2016Co-Authors: Li Xiao, Xiaoxuan Xu, Dan Tang, Yan Xu, Jiahui Wang, Ming Wang, Fan Zhang, Chengyuan TangAbstract:Mitochondria play a crucial role in tubular injury in diabetic kidney disease (DKD). MitoQ is a mitochondria-targeted antioxidant that exerts protective effects in diabetic mice, but the mechanism underlying these effects is not clear. We demonstrated that mitochondrial abnormalities, such as defective mitophagy, mitochondrial reactive oxygen species (ROS) overexpression and mitochondrial fragmentation, occurred in the tubular cells of db/db mice, accompanied by reduced PINK and Parkin expression and increased apoptosis. These changes were partially reversed following an intraperitoneal injection of MitoQ. High glucose (HG) also induces deficient mitophagy, mitochondrial dysfunction and apoptosis in HK-2 cells, changes that were reversed by MitoQ. Moreover, MitoQ restored the expression, activity and translocation of HG-induced NF-E2-related factor 2 (Nrf2) and inhibited the expression of Kelch-like ECH-associated protein (Keap1), as well as the interaction between Nrf2 and Keap1. The reduced PINK and Parkin expression noted in HK-2 cells subjected to HG exposure was partially restored by MitoQ. This effect was abolished by Nrf2 siRNA and augmented by Keap1 siRNA. Transfection with Nrf2 siRNA or PINK siRNA in HK-2 cells exposed to HG conditions partially blocked the effects of MitoQ on mitophagy and tubular damage. These results suggest that MitoQ exerts beneficial effects on tubular injury in DKD via mitophagy and that mitochondrial quality control is mediated by Nrf2/PINK.