Free radical damage, vulnerability

Free radicals seek to combine with electrons from stable compounds and thus produce more free radicals in the process. The cell membrane is one of the most vulnerable structures to free radical damage. Also affected are low-density lipoproteins, other proteins, and DNA. Free radicals alter functions of these molecules or cause mutations in DNA. There are mechanisms in place to repair free radical damage, but the repair is not completely effective and becomes less so with age. The result is heart disease, cancer, arthritis, cataracts, and aged skin (Elson, 2009). 

These free radicals are extremely reactive and capable of attacking cell constituents. Polyunsaturated fatty acids found in membrane phospholipids, proteins, and nucleic acids are all vulnerable targets (Pietrangelo, 1998). Cellular antioxidant defenses exist to breakdown ROS. Owing to these defenses, a severe iron burden is necessary to cause damage (Pietrangelo, 2002). 

Radical generation at inappropriate sites may thus lead to protein destruction since they are also critical targets for free radical attack, both intracellularly and extracellularly. Proteins may be directly damaged, by specific interactions of oxidants or free radicals with particularly susceptible amino acids. Several amino acyl constituents crucial for a protein s function are particularly vulnerable to radical damage (Fig. 4) [21,22]. 

Vulnerability of proteins to radical-mediated damage Proteins are critical targets for free radical attack, both intracellularly and extra-cellularly and, because many are catalytic, modifications may have an amplified effect. 

Kuriyama H, Waki M, Nakagawa M, Tsuda M. 2001. Involvement of oxygen free radicals in experimental retinal ischemia and the selective vulnerability of retinal damage. Ophthalmic Res 33 196-202. 

A basic molecular step on the pathway of neuronal damage is dysfunction of the mitochondrial complex I. MPTP, rotenone and paraquat are toxins inhibiting complex I. Inhibition leads to the formation of free radicals and, as a consequence, oxidative stress, which makes the cells vulnerable to glutamate excitotoxicity. Complex I dysfunction may also mediate ceU death via caspase-dependent and caspase-indepen-dent apoptosis, necrosis, and inflammation-induced injury [15, 16]. 

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