This review examines the generation of reactive oxygen species by mammalian mitochondria, and the status of different sites of production in redox signaling and pathology. Eleven distinct ...mitochondrial sites associated with substrate oxidation and oxidative phosphorylation leak electrons to oxygen to produce superoxide or hydrogen peroxide: oxoacid dehydrogenase complexes that feed electrons to NAD+; respiratory complexes I and III, and dehydrogenases, including complex II, that use ubiquinone as acceptor. The topologies, capacities, and substrate dependences of each site have recently clarified. Complex III and mitochondrial glycerol 3-phosphate dehydrogenase generate superoxide to the external side of the mitochondrial inner membrane as well as the matrix, the other sites generate superoxide and/or hydrogen peroxide exclusively in the matrix. These different site-specific topologies are important for redox signaling. The net rate of superoxide or hydrogen peroxide generation depends on the substrates present and the antioxidant systems active in the matrix and cytosol. The rate at each site can now be measured in complex substrate mixtures. In skeletal muscle mitochondria in media mimicking muscle cytosol at rest, four sites dominate, two in complex I and one each in complexes II and III. Specific suppressors of two sites have been identified, the outer ubiquinone-binding site in complex III (site IIIQo) and the site in complex I active during reverse electron transport (site IQ). These suppressors prevent superoxide/hydrogen peroxide production from a specific site without affecting oxidative phosphorylation, making them excellent tools to investigate the status of the sites in redox signaling, and to suppress the sites to prevent pathologies. They allow the cellular roles of mitochondrial superoxide/hydrogen peroxide production to be investigated without catastrophic confounding bioenergetic effects. They show that sites IIIQo and IQ are active in cells and have important roles in redox signaling (e.g. hypoxic signaling and ER-stress) and in causing oxidative damage in a variety of biological contexts.
•The generation of O⋅−2 and H2O2 by mammalian mitochondria is reviewed.•The topologies and capacities of 11 different sites are known.•In skeletal muscle mitochondria four sites dominate under physiological conditions.•There are specific suppressors of two sites that have no bioenergetic effects.•The cellular roles of mitochondrial O⋅−2 and H2O2 production are discussed.
Mitochondrial superoxide production is an important source of reactive oxygen species in cells, and may cause or contribute to ageing and the diseases of ageing. Seven major sites of superoxide ...production in mammalian mitochondria are known and widely accepted. In descending order of maximum capacity they are the ubiquinone-binding sites in complex I (site IQ) and complex III (site IIIQo), glycerol 3-phosphate dehydrogenase, the flavin in complex I (site IF), the electron transferring flavoprotein:Q oxidoreductase (ETFQOR) of fatty acid beta-oxidation, and pyruvate and 2-oxoglutarate dehydrogenases. None of these sites is fully characterized and for some we only have sketchy information. The topology of the sites is important because it determines whether or not a site will produce superoxide in the mitochondrial matrix and be able to damage mitochondrial DNA. All sites produce superoxide in the matrix; site IIIQo and glycerol 3-phosphate dehydrogenase also produce superoxide to the intermembrane space. The relative contribution of each site to mitochondrial reactive oxygen species generation in the absence of electron transport inhibitors is unknown in isolated mitochondria, in cells or in vivo, and may vary considerably with species, tissue, substrate, energy demand and oxygen tension.
Assessing mitochondrial dysfunction requires definition of the dysfunction to be investigated. Usually, it is the ability of the mitochondria to make ATP appropriately in response to energy demands. ...Where other functions are of interest, tailored solutions are required. Dysfunction can be assessed in isolated mitochondria, in cells or in vivo, with different balances between precise experimental control and physiological relevance. There are many methods to measure mitochondrial function and dysfunction in these systems. Generally, measurements of fluxes give more information about the ability to make ATP than do measurements of intermediates and potentials. For isolated mitochondria, the best assay is mitochondrial respiratory control: the increase in respiration rate in response to ADP. For intact cells, the best assay is the equivalent measurement of cell respiratory control, which reports the rate of ATP production, the proton leak rate, the coupling efficiency, the maximum respiratory rate, the respiratory control ratio and the spare respiratory capacity. Measurements of membrane potential provide useful additional information. Measurement of both respiration and potential during appropriate titrations enables the identification of the primary sites of effectors and the distribution of control, allowing deeper quantitative analyses. Many other measurements in current use can be more problematic, as discussed in the present review.
Polymers are ubiquitously present in our daily life because they can meet a wide range of needs and fields of applications. This success, based on an irresponsible linear consumption of plastics and ...the access to cheap oil, is creating serious environmental problems. Two lines of actions are needed to cope with them: to adopt a circular consumption of plastics and to produce renewable carbon-neutral monomers. This review analyses the recent advances in the chemocatalytic processes for producing biomass-derived carboxylic acids. These renewable carboxylic acids are involved in the synthesis of relevant general purpose and specialty polyesters and polyamides; some of them are currently derived from oil, while others can become surrogates of petrochemical polymers due to their excellent performance properties. Polyesters and polyamides are very suitable to be depolymerised to other valuable chemicals or to their constituent monomers, what facilitates the circular reutilisation of these monomers. Different types of carboxylic acids have been included in this review: monocarboxylic acids (like glycolic, lactic, hydroxypropanoic, methyl vinyl glycolic, methyl-4-methoxy-2-hydroxybutanoic, 2,5-dihydroxypent-3-enoic, 2,5,6-trihydroxyhex-3-enoic acids, diphenolic, acrylic and δ-amino levulinic acids), dicarboxylic acids (2,5-furandicarboxylic, maleic, succinic, adipic and terephthalic acids) and sugar acids (like gluconic and glucaric acids). The review evaluates the technology status and the advantages and drawbacks of each route in terms of feedstock, reaction pathways, catalysts and economic and environmental evaluation. The prospects and the new research that should be undertaken to overcome the main problems threatening their economic viability or the weaknesses that prevent their commercial implementation have also been underlined.
This review revises the advances in the chemocatalytic processes for producing renewable carboxylic acids for the synthesis of bio-based polymers and proposes the actions to overcome the problems threatening their technical and economic viability.
Today we are poised for a transition from the highly customized crafting of specific molecular targets by hand to the increasingly general and automated assembly of different types of molecules with ...the push of a button. Creating machines that are capable of making many different types of small molecules on demand, akin to that which has been achieved on the macroscale with 3D printers, is challenging. Yet important progress is being made toward this objective with two complementary approaches: 1) Automation of customized synthesis routes to different targets by machines that enable the use of many reactions and starting materials, and 2) automation of generalized platforms that make many different targets using common coupling chemistry and building blocks. Continued progress in these directions has the potential to shift the bottleneck in molecular innovation from synthesis to imagination, and thereby help drive a new industrial revolution on the molecular scale.
Automation is enabling a new Industrial Revolution, this time on the molecular scale. This Minireview provides insights into the ongoing transition from manual to automated organic synthesis. Akin to a 3D printer for molecules, continued progress in this frontier area will democratize innovation on the molecular scale and shift the rate‐limiting step in new molecular function discovery from synthesis to imagination.
Elevated mitochondrial matrix superoxide and/or hydrogen peroxide concentrations drive a wide range of physiological responses and pathologies. Concentrations of superoxide and hydrogen peroxide in ...the mitochondrial matrix are set mainly by rates of production, the activities of superoxide dismutase-2 (SOD2) and peroxiredoxin-3 (PRDX3), and by diffusion of hydrogen peroxide to the cytosol. These considerations can be used to generate criteria for assessing whether changes in matrix superoxide or hydrogen peroxide are both necessary and sufficient to drive redox signaling and pathology: is a phenotype affected by suppressing superoxide and hydrogen peroxide production; by manipulating the levels of SOD2, PRDX3 or mitochondria-targeted catalase; and by adding mitochondria-targeted SOD/catalase mimetics or mitochondria-targeted antioxidants? Is the pathology associated with variants in SOD2 and PRDX3 genes? Filtering the large literature on mitochondrial redox signaling using these criteria highlights considerable evidence that mitochondrial superoxide and hydrogen peroxide drive physiological responses involved in cellular stress management, including apoptosis, autophagy, propagation of endoplasmic reticulum stress, cellular senescence, HIF1α signaling, and immune responses. They also affect cell proliferation, migration, differentiation, and the cell cycle. Filtering the huge literature on pathologies highlights strong experimental evidence that 30-40 pathologies may be driven by mitochondrial matrix superoxide or hydrogen peroxide. These can be grouped into overlapping and interacting categories: metabolic, cardiovascular, inflammatory, and neurological diseases; cancer; ischemia/reperfusion injury; aging and its diseases; external insults, and genetic diseases. Understanding the involvement of mitochondrial matrix superoxide and hydrogen peroxide concentrations in these diseases can facilitate the rational development of appropriate therapies.
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Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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