M P Murphy

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..Here we review the background and work to date on this class of mitochondria-targeted antioxidants...

..This combination of a hierarchical framework and the methodologies of MCA may prove useful both for thinking about aging and for analyzing it experimentally...

..The selective mitochondrial localization of these compounds enables us to investigate several aspects of the production of reactive oxygen species by mitochondria...

..Here we outline some of the background to the development of these compounds...

..These data resolve reported discrepancies on the effect of NO on HIF-1alpha stability at low oxygen concentrations and suggest that inhibition of mitochondrial respiration by NO may affect oxygen sensing by HIF-1 in vivo...

..Superoxide releases iron from iron-sulfur center proteins, which then generates carbon-centered radicals that initiate lipid peroxidation, yielding breakdown products that activate UCPs...

..Mitochondria-targeted lipophilic cations may lead to improved therapies for diseases involving mitochondrial dysfunction...

..Our results comprehensively describe the interaction of exogenous ubiquinones with mitochondria and have implications for their rational design and use as therapies and as research tools to probe mitochondrial function...

..We conclude that superoxide (or its products) exerts its uncoupling effect by activating the proton transport mechanism of uncoupling proteins at the matrix side of the mitochondrial inner membrane...

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..Here we review why these molecules are useful in mitochondrial research and outline some of the ways in which they are now being utilized...

..Furthermore, as TEMPOL is also reduced to a hydroxylamine in vivo, many of its antioxidant effects may also be mediated by its hydroxylamine...

..Here, we outline how the formation and consequences of mitochondrial ROS production can be investigated using these probes...

..This inability to alkylate mtDNA in situ has significant implications for the design of therapies for mtDNA diseases and for studies on the packaging, expression and turnover of mtDNA in general...

..Instead, this suggests that it may be possible to form dications within mitochondria that then remain within the cell...

..MitoQ protects mitochondria against oxidative damage in vitro and following oral delivery, and may therefore form the basis for mitochondria-protective therapies...

..In the present study, we review the mechanisms and physiological significance of these processes...

..Therefore, mitochondria-targeted single-chain ZFNs are a promising candidate approach for the treatment of mtDNA diseases...

..Our findings indicate that Grx2 plays a central role in the response of mitochondria to both redox signals and oxidative stress by facilitating the interplay between the mitochondrial glutathione pool and protein thiols...

..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...

..These results suggest that the protective action of LA in vivo may require its reduction to LAH(2) and that this reduction is largely mediated by TrxR...

..These findings will facilitate the rational design of future mitochondria-targeted molecules...

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..This is a proof of principle that it is possible to target and alter mtDNA in a sequence-specific manner by using zinc finger technology...

..The strong influence of hydrophobicity on TPP cation uptake into mitochondria within cells facilitates the rational design of mitochondria-targeted compounds to report on and modify mitochondrial function in vivo...

..The protocol can be completed within a week, although time-consuming DNA cloning steps may extend this...

..Using a DeltaCoQ double-knockout library we identified a number of genes that decrease the ability of yeast to grow on exogenous CoQ. Here we suggest that CoQ or its redox state may be a signal for growth during the shift to respiration...

..Together this membrane potential-dependent uptake across the mitochondrial inner membrane and the subsequent rapid reduction to the paraquat radical cation explain the toxicity of paraquat to mitochondria...

..These findings point to a significant role for complex I S-nitrosation and consequent dysfunction during nitrosative stress in disorders such as Parkinson disease and sepsis...

..More generally, the development of SNO-DIGE facilitates robust investigation of protein S-nitrosation across the proteome...

..Here, we outline the background to these strategies and discuss how antioxidants targeted to mitochondria, or selective mitochondrial uncoupling, may be potential therapies for diabetes...

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..Thus, the potential benefits in neurodegenerative diseases of some classes of antioxidants may be compromised by their autophagy-blocking properties...

..To help understand how Coenzyme Q contributes to both mitochondrial oxidative damage and antioxidant defences, we have reviewed its antioxidant and prooxidant properties...

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..Here we outline some of the approaches that can be used to accomplish these goals and thereby infer the multiple roles of mammalian mitochondrial protein thiols in antioxidant defense and redox signaling...

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..This finding opens the way to the testing of mitochondria-specific therapies in mouse models of human degenerative diseases...

..Thiol redox modification affected enzyme activity, suggesting that the reversible modification of enzyme activity by ROS from the respiratory chain may be an important and unexplored mode of mitochondrial redox signaling...

..Here we review mitochondrial thiol metabolism, outline how NO and its metabolites interact with thiols, and discuss the implications of these reactions for mitochondrial and cell function...

..Here we review the mechanisms and physiological significance of the glutathionylation of mitochondrial thiol proteins...

..A better understanding of these processes will eventually clarify why particular mtDNA mutations cause defined syndromes in some cases but not in others and why the same mutation can lead to different phenotypes...

..These results support the idea that selectively targeting NO(*) donors to mitochondria is an effective strategy to reversibly modulate respiration and to protect mitochondria against ischemia-reperfusion injury...

..This result suggests that CPPs are unsuitable as mitochondria-targeting vectors, and implies an endocytic mode of cellular uptake for CPPs...

..Therefore, exposed protein thiols are the dominant free thiol within the cell and may play a critical role in intracellular antioxidant defences against oxidative damage...

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..DNA damage is present in both genomic and mitochondrial DNA in atherosclerosis. However, whether DNA damage itself promotes atherosclerosis, or is simply a byproduct of the risk factors that promote atherosclerosis, is unknown...

..These findings are consistent with roles for mitochondrial vicinal dithiol proteins in antioxidant defence and redox signalling and these methodologies will enable these roles to be explored...

..This exploration has led to new insights into the behavior of peroxidase mimetics within mitochondria and to their use in investigating mitochondrial oxidative damage...

..This method of directing PNAs into cells is a significant improvement on current procedures and will facilitate in vitro and pharmacological applications of PNAs...

..Importantly, this method is not only applicable to studies in isolated mitochondria but can also be applied to more complicated systems such as intact cells and perhaps even whole organisms...

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..Therefore, the mitochondrial redox state appears to modulate a nuclear-driven biochemical event, i.e., transcriptional activation of a nuclear gene encoding a protein targeted to mitochondria...

..These results show that mitochondria are an important source of toxic oxygen radicals in blue light-exposed RPE cells and may indicate new approaches for treating AMD using mitochondria-targeted antioxidants...

..These data establish a novel role for the mitochondrion as a proximal target specific to H(2)O(2)-induced signaling and growth factor transactivation...

..This study unveils a new and unexplored aspect of the participation of mitochondria in calcium signals...

..Targeted antioxidants may have therapeutic potential in FRDA and in other disorders involving mitochondrial oxidative damage...

..We conclude that the reactivities of PQQ are dependent on its environment and that it can act as an antioxidant or a pro-oxidant in different biological systems...

..When fed to mice these compounds accumulated within the brain, heart, and liver; therefore, using these mitochondrial-targeted antioxidants may help investigations of the role of mitochondrial oxidative damage in animal models of aging...

..In addition the methodology has the potential to identify novel redox-dependent modulation of mitochondrial proteins...

..Therefore MitoDNP did not act as a protonophore, probably because the efflux of deprotonated MitoDNP was inhibited...

..This study strongly suggests that mitochondrial ROS contribute to the hypoxic stabilization of HIF-1alpha...

..These findings place significant constraints on the role of oxidative stress in normal ageing...

..These results provide genetic and pharmacologic evidence that the Qo site of complex III is required for the transduction of hypoxic signal by releasing ROS to stabilize the HIF-1alpha protein...

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..The compromised activity of MnSOD, a primary antioxidant enzyme protecting mitochondria, may explain mitochondrial dysfunction and provide the missing link between Abeta-induced oxidative stress and Alzheimer's disease...

..This newly recognized, receptor-independent mechanism of serotonin may contribute to myocardial remodeling and failure...

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..Monitoring oxidation at both 396 and 510 nm of excitation wavelengths can facilitate the more selective detection of superoxide in vivo...

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..The results also suggest that mitochondrial oxidative damage does not contribute significantly to the death of striatal medium-spiny neurons after perinatal hypoxia-ischemia...

..However, many of these agents have not yet been tested in clinical trials and studies are urgently needed to determine efficacy, safety, optimal dosage and time of administration...

..The availability of two electron pathways in C. albicans and the potential use of either pathway endows this pleomorphic fungus with another level at which it can rapidly adjust to altered environmental conditions...

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..Instead, these results suggest alternative mitochondrial functions, such as a respiration-dependent process, are critical for necrotic death...