ABSTRACT
It is now commonly recognized that oxygen radicals, and free radicals in general, are involved in a variety of physiological and pathological processes in organisms, including cellular signaling, cell proliferation and differentiation, apoptosis, cancer, and AIDS, as well as other diseases such as ischemia-reperfusion injury, inflammation, and degenerative diseases, and in senescence (1-3,33,34). One of the consistent sources of oxygen radicals among tissues is the mitochondrial respiratory chain, especially at the flavoprotein and ubiquinone-cytochrome b segments. When electron transfer from substrate to dioxygen proceeds along the respiratory chain, not all the oxygen is tetravalently reduced to form water via cytochrome oxidase. Instead, a small portion of oxygen molecules can accept single-electron transfer to form superoxide radicals (O2 ) by the so-called "electron univalent leak," or "electron leak," pathway. In general, only 2-4% of oxygen consumed is partially reduced to O2" (and H2O2) (1,10-13), and the daily yield of O2~ might reach 107 molecules per mitochondrion (2). Under normal physiological conditions, the superoxide radicals in the mitochondria can be destroyed by Mn2+-superoxide dismutase (Mn-SOD) and other scavenging enzymes. However, the activities of the enzymes decrease with the development of disease and with aging, and the O ^ are accumulated in mitochondria, resulting in dysfunction of mitochondria and mtDNA alteration (1-3). It is also known that more than one hundred human mitochondrial diseases are related to mitochondrial dysfunction and mutations of mtDNA, in which reactive oxygen species might be involved (4-6). It is therefore of importance to study the mechanism of O^~ generation and targeting and its pathophysiological functions in mitochondria.
