The production of ROS (reactive oxygen species) by mammalian mitochondria is important because it underlies oxidative damage in many pathologies and contributes to retrograde redox signalling from ...the organelle to the cytosol and nucleus. Superoxide (O2(*-)) is the proximal mitochondrial ROS, and in the present review I outline the principles that govern O2(*-) production within the matrix of mammalian mitochondria. The flux of O2(*-) is related to the concentration of potential electron donors, the local concentration of O2 and the second-order rate constants for the reactions between them. Two modes of operation by isolated mitochondria result in significant O2(*-) production, predominantly from complex I: (i) when the mitochondria are not making ATP and consequently have a high Deltap (protonmotive force) and a reduced CoQ (coenzyme Q) pool; and (ii) when there is a high NADH/NAD+ ratio in the mitochondrial matrix. For mitochondria that are actively making ATP, and consequently have a lower Deltap and NADH/NAD+ ratio, the extent of O2(*-) production is far lower. The generation of O2(*-) within the mitochondrial matrix depends critically on Deltap, the NADH/NAD+ and CoQH2/CoQ ratios and the local O2 concentration, which are all highly variable and difficult to measure in vivo. Consequently, it is not possible to estimate O2(*-) generation by mitochondria in vivo from O2(*-)-production rates by isolated mitochondria, and such extrapolations in the literature are misleading. Even so, the description outlined here facilitates the understanding of factors that favour mitochondrial ROS production. There is a clear need to develop better methods to measure mitochondrial O2(*-) and H2O2 formation in vivo, as uncertainty about these values hampers studies on the role of mitochondrial ROS in pathological oxidative damage and redox signalling.
Mitochondrial oxidative damage has long been known to contribute to damage in conditions such as ischaemia-reperfusion (IR) injury in heart attack. Over the past years, we have developed a series of ...mitochondria-targeted compounds designed to ameliorate or determine how this damage occurs. I will outline some of this work, from MitoQ to the mitochondria-targeted S-nitrosating agent, called MitoSNO, that we showed was effective in preventing reactive oxygen species (ROS) formation in IR injury with therapeutic implications. In addition, the protection by this compound suggested that ROS production in IR injury was mainly coming from complex I. This led us to investigate the mechanism of the ROS production and using a metabolomic approach, we found that the ROS production in IR injury came from the accumulation of succinate during ischaemia that then drove mitochondrial ROS production by reverse electron transport at complex I during reperfusion. This surprising mechanism led us to develop further new therapeutic approaches to have an impact on the damage that mitochondrial ROS do in pathology and also to explore how mitochondrial ROS can act as redox signals. I will discuss how these approaches have led to a better understanding of mitochondrial oxidative damage in pathology and also to the development of new therapeutic strategies.
'Reactive oxygen species' (ROS) is a generic term that defines a wide variety of oxidant molecules with vastly different properties and biological functions that range from signalling to causing cell ...damage. Consequently, the description of oxidants needs to be chemically precise to translate research on their biological effects into therapeutic benefit in redox medicine. This Expert Recommendation article pinpoints key issues associated with identifying the physiological roles of oxidants, focusing on H
O
and O
. The generic term ROS should not be used to describe specific molecular agents. We also advocate for greater precision in measurement of H
O
, O
and other oxidants, along with more specific identification of their signalling targets. Future work should also consider inter-organellar communication and the interactions of redox-sensitive signalling targets within organs and whole organisms, including the contribution of environmental exposures. To achieve these goals, development of tools that enable site-specific and real-time detection and quantification of individual oxidants in cells and model organisms are needed. We also stress that physiological O
levels should be maintained in cell culture to better mimic in vivo redox reactions associated with specific cell types. Use of precise definitions and analytical tools will help harmonize research among the many scientific disciplines working on the common goal of understanding redox biology.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Mitochondrial dysfunction is often associated with increased reactive oxygen species (ROS) production by the organelle itself. Leadsham et al. (2013) now show that the link between mitochondrial ...damage and ROS is more complicated, at least in yeast, where signals from damaged mitochondria increase ROS production from the endoplasmic reticulum surface.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The mitochondrial matrix contains much of the machinery at the heart of metabolism. This compartment is also exposed to a high and continual flux of superoxide, hydrogen peroxide, and related ...reactive species. To protect mitochondria from these sources of oxidative damage, there is an integrated set of thiol systems within the matrix comprising the thioredoxin/peroxiredoxin/methionine sulfoxide reductase pathways and the glutathione/glutathione peroxidase/glutathione-S-transferase/glutaredoxin pathways that in conjunction with protein thiols prevent much of this oxidative damage. In addition, the changes in the redox state of many components of these mitochondrial thiol systems may transduce and relay redox signals within and through the mitochondrial matrix to modulate the activity of biochemical processes.
Here, mitochondrial thiol systems are reviewed, and areas of uncertainty are pointed out, focusing on recent developments in our understanding of their roles.
The areas of particular focus are on the multiple, overlapping roles of mitochondrial thiols and on understanding how these thiols contribute to both antioxidant defenses and redox signaling.
Recent technical progress in the identification and quantification of thiol modifications by redox proteomics means that many of the questions raised about the multiple roles of mitochondrial thiols can now be addressed.
Targeting lipophilic cations to mitochondria Murphy, Michael P.
Biochimica et biophysica acta,
July-August 2008, 2008 Jul-Aug, 2008-07-00, Volume:
1777, Issue:
7-8
Journal Article
Peer reviewed
Open access
Mitochondrial function and dysfunction contributes to a range of important aspects of biomedical research. Consequently there is considerable interest in developing approaches to modify and report on ...mitochondria in cells and in vivo. One approach has been to target bioactive molecules to mitochondria by conjugating them to lipophilic cations. Due to the large mitochondrial membrane potential, the cations are accumulated within mitochondria inside cells. This approach had been used to develop mitochondria-targeted antioxidants that selectively block mitochondrial oxidative damage and prevent some types of cell death and also to develop probes of mitochondrial function. Here we outline some of the background to the development of these compounds.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The COVID-19 pandemic quickly led to the closure of universities and colleges around the world, in hopes that public health officials' advice of social distancing could help to flatten the infection ...curve and reduce total fatalities from the disease. Drawing on Copenhagen school securitization theory and analyzing 25 declarations of emergency eLearning at American universities, I argue that in addition to COVID-19 being framed as a general threat, face-to-face schooling was also presented as a threat through these policies. A review of securitization theory-with particular attention to the question of advocacy and the relationship of desecuritization to emancipation-grounds the investigation theoretically. I argue that securitization theory is an important tool for educators not only for observing (and understanding) the phenomenon of emergency eLearning, but also for advocating the desecuritization of schooling after the COVID-19 crisis passes.
Full text
Available for:
BFBNIB, NUK, PILJ, SAZU, UL, UM, UPUK
Krebs cycle intermediates traditionally link to oxidative phosphorylation whilst also making key cell components. It is now clear that some of these metabolites also act as signals. Succinate plays ...an important role in inflammatory, hypoxic, and metabolic signaling, while itaconate (from another Krebs cycle intermediate, cis-aconitate) has an anti-inflammatory role.
The metabolites succinate and itaconate have emerged as key signaling molecules linking mitochondrial function to the rest of the cell across several areas of cell function.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Ischemia-reperfusion (IR) injury occurs when blood supply to an organ is disrupted—ischemia—and then restored—reperfusion—leading to a burst of reactive oxygen species (ROS) from mitochondria. It has ...been tacitly assumed that ROS production during IR is a non-specific consequence of oxygen interacting with dysfunctional mitochondria upon reperfusion. Recently, this view has changed, suggesting that ROS production during IR occurs by a defined mechanism. Here we survey the metabolic factors underlying IR injury and propose a unifying mechanism for its causes that makes sense of the huge amount of disparate data in this area and provides testable hypotheses and new directions for therapies.
Ischemia-reperfusion (IR) injury occurs when circulation is disrupted and then restarted. Chouchani et al. propose a unifying framework for an array of data that could explain how ROS is specifically produced during IR, this providing testable hypotheses and new directions for therapies.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Although oxidative damage contributes to many pathologies the use of naturally occurring, small-molecule antioxidants as therapies for these disorders has not been successful. Here I discuss some of ...the reasons this may be so. Paramount among these are the difficulties in delivering enough of the antioxidant to the intracellular location required to decrease pathological oxidative damage and the challenge of assessing whether the intervention has actually decreased oxidative damage in the patient to a therapeutically useful extent. To develop effective antioxidant therapies the best strategy may be to create new chemical entities designed to detoxify a defined reactive oxygen species-dependent process that underlies a particular pathology, in the same way a conventional drug is designed to modulate a biochemical process, rather than applying antioxidants in an unfocused manner. In developing new antioxidants it will be useful to utilize endogenous processes to activate and recycle the molecules in parallel with the targeting of compounds to cells and organelles in ways that are not limited by the constraints that impair the distribution of endogenous antioxidants. In short, I suggest that the future development of antioxidant therapies should be viewed as an arm of drug development, utilizing focused approaches similar to those of medicinal chemistry and pharmacology, rather than as a branch of nutrition.
Display omitted
•Antioxidants have been relatively poor therapies.•It is difficult to assess how well antioxidants work in vivo.•Lack of efficacy is in part due to antioxidants not concentrating in the parts of the cell where they are needed.•A way forward is to use medicinal chemistry to make more effective artificial antioxidants.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK