Mitochondrial targeting of electron scavenging antioxidants: Regulation of selective oxidation vs random chain reactions☆
Section snippets
Introduction: selective oxidation vs random chain reactions of lipid peroxidation
The remarkable success of chemistry in understanding the mechanisms and kinetics of chain reactions in the gas phase [1], [2] and the subsequent demonstration of these ideas for chemical oxidation reactions in the liquid phase [3] created a supposition that free radical chain oxidation reactions can also take place in biological systems. This resulted in the appearance of several novel hypotheses on the free radical mechanisms of aging [4], [5] and radiation injury [6] as well as their role in
ROS reactivity: specific enzyme-dependent ROS signaling vs random free radical damage
ROS – formed during one-electron reduction of oxygen – are believed to be essential for the initiation of free radical reactions. They are commonly viewed as nonspecific oxidants capable of inducing oxidation of practically any biological molecule (proteins, lipids, DNA) via free radical pathways [31]. Yet, direct interactions of ROS (namely, O2·– and H2O2) with lipids and reactive groups of proteins are slow and inefficient. For example, the rate of the reaction of H2O2 with unsaturated lipids
Mitochondrial peroxidation reactions — catalysis and role of the electron transport chain (ETC)
An alternative view on the ROS production and functions in cells suggests that they are involved in specific, compartmentalized and controlled catalytic reactions. What are the known major sites of radical production and oxidative stress? There are multiple possible site-specific sources of oxidizing equivalents and enzymes with high oxidizing potential that may participate in the generation of oxygen radicals. NADPH oxidases in the plasma membrane of inflammatory cells are potent producers of O
Mitochondrial targeted delivery of oxidation regulators: major principles
Because a large number of human diseases may be associated with mitochondrial dysfunction [69], [70], there is an emerging field of biomedical research – “mitochondrial medicine” – that includes pharmacological approaches to control and correct de-regulated mitochondria [71], [72]. This research stimulated the development of methods for mitochondrial drug delivery for selective protection, repair, or even eradication (in cases of irreparable damage) of mitochondria.
Cells routinely utilize
Mitochondrial targeted delivery of antioxidant enzymes
As mentioned above, targeted mitochondrial delivery of proteins, including antioxidant enzymes, can be achieved via expression of leader sequences directing the proteins into mitochondria. Herein, we will describe a series of elegant experiments illustrating the successful application of this principle with regards to protection of cells and animals by SOD and catalase against oxidative stress induced by ionizing irradiation.
Mitochondrial targeting of both transgene products [79], [87] and
Chemistry of small molecule targeted delivery into mitochondria
Selective delivery is key to eliciting desirable therapeutic effects in diseases that originate from mitochondrial dysfunction [92]. Most targeting agents profit from the negative potential of mitochondria. The process of electron transfer to O2 is coupled to a proton gradient that drives ATP production and generates a negative potential of − 150 to − 180 mV across the inner mitochondrial membrane [93]. Furthermore, the permeability of the outer membrane to small organic molecules facilitates the
Concluding remarks
A diversified set of principles and chemically or biosynthetically synthesized delivery tools offers broad opportunities to achieving differential levels of enrichment or impoverishment of regulators of choice in different types of cells — tumor cells, surrounding normal cells as well as in their compartments. This may be important not only for stimulated sensitization of tumor cells towards pro-apoptotic agents (chemotherapeutics, irradiation) but also for increased resistance of surrounding
Acknowledgements
This work was supported by NIH Grants U19 AIO68021, HL70755, HD057587, NS061817, NORA 927Z1LU, PittGrid (http://www.pittgrid.pitt.edu) and la Junta de Extremadura -Consejeria de Infraestructuras y Desarrollo Tecnologico- y el Fondo Social Europeo (Orden 2008050288).
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Mitochondrial Medicine and Therapeutics, Part II”.