Sources of Free Radicals

Free radicals are continuously produced from various biological processes regulated by a variety of enzymes in multiple subcellular compartments within the cell (49). Under normal physiological conditions, most of the cellular ROS are generated in the mitochondria through "leakage" of oxidative phosphorylation, a biological process that produces ATP, the major form of energy in cells. Nicotinamide adenine dinucleotide (NADH) or flavin adenine dinucleotide (FADH), the reduced form of coenzymes for a variety of biochemical reactions in the cell, facilitates the formation of ATP, responsible for energy-transfer reactions. In oxidative phosphorylation, the electrons from NADH or FADH flow sequentially through a mobile electron acceptor such as coenzyme Q, and through acceptors such as cytochrome c1 and cytochrome c, which form protein complexes I to IV in mitochondria. The electrons are then transferred to molecular oxygen to form water and produce a proton gradient, which is used to generate portable ATP energy via the F1-F0 ATPase. During the transferring processes, some of the electrons are "leaked" out of the mitochondrial protein complexes and are absorbed directly by molecular oxygen to generate superoxide radical (O2-). The "leakage" occurs predominantly in two complexes, complexes I and III, where the potential energy of the electrons has large changes relative to the reduction of oxygen (49). The rate of ROS generation in the mitochondria is believed to be regulated by

1. the reduction-oxidation (redox) potential of these complexes, that is, the ability of a redox couple to accept or donate electrons,

2. the oxygen tension, and

3. the number of electron-transfer sites (48).

In addition to the mitochondria, ROS can also be produced in other subcellular compartments and by multiple enzymes. These include enzymes within the plasma membrane, such as NAD(P)H oxidase (50), and peroxisomal oxidases in peroxisomes (51). Endogenous biological processes such as oxidative phosphorylation as well as various exogenous stimuli such as radiation, exposure to toxins, pathogen infections, heat, and ultraviolet light regulate ROS production (52-54).

NO is an important free radical of RNS and is produced predominantly through oxidative deamination of L-arginine by NO synthase in the cell (48,55,56). Not much is known about regulation of RNS production in the cell. However, when NO is produced in excess, it can react with ROS to generate reactive peroxynitrite, which, in turn, can be broken down into nitric dioxide and highly reactive hydroxyl radicals.

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