Elsevier

Advanced Drug Delivery Reviews

Volume 61, Issue 14, 30 November 2009, Pages 1375-1385
Advanced Drug Delivery Reviews

Mitochondrial targeting of electron scavenging antioxidants: Regulation of selective oxidation vs random chain reactions

https://doi.org/10.1016/j.addr.2009.06.008Get rights and content

Abstract

Effective regulation of highly compartmentalized production of reactive oxygen species and peroxidation reactions in mitochondria requires targeting of small molecule antioxidants and antioxidant enzymes into the organelles. This review describes recently developed approaches to mitochondrial targeting of small biologically active molecules based on: (i) preferential accumulation in mitochondria because of their hydrophobicity and positive charge (hydrophobic cations), (ii) binding with high affinity to an intra-mitochondrial constituent, and (iii) metabolic conversions by specific mitochondrial enzymes to reveal an active entity. In addition, targeted delivery of antioxidant enzymes via expression of leader sequences directing the proteins into mitochondria is considered. Examples of successful antioxidant and anti-apoptotic protection based on the ability of targeted cargoes to inhibit cytochrome c-catalyzed peroxidation of a mitochondria-specific phospholipid cardiolipin, in vitro and in vivo are presented. Particular emphasis is placed on the employment of triphenylphosphonium- and hemi-gramicidin S-moieties as two effective vehicles for mitochondrial delivery of antioxidants.

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”.

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