One of the first reports of mitochondrial ROS production came from Boveris and Chance , who used antimycin A, an inhibitor of the mitochondrial electron transport chain (ETC) complex III, to induce O- and H2O2 generation. Since then, it has not only become evident that mitochondria are capable of low levels of ROS production during normal physiology [29, 30], but ROS are critical factors in a number of different signaling pathways involved in apoptosis .
Mitochondrial ROS generation is an unavoidable by-product of oxidative phosphorylation due to the nature of reduction-oxidation reactions that occur during generation of the proton gradient across the inner mitochondrial membrane. It is recognized that the two major sites of ROS production arise from the autooxidation of intermediate semiquinones at either complexes I or III . The semiquinones at these sites are nonenzymatically oxidized by molecular O2 to yield O- .
The majority of mitochondrial O- is released into the matrix and the rest into the intermembrane space where it is rapidly converted to H2O2 by superoxide dismutase (SOD).
Three different nitric oxide synthases (NOS) have been identified in mammals: neuronal NOS (nNOS), inducible or macrophage NOS (iNOS), and endothelial NOS (eNOS). The mitochondrial NOS (mtNOS) has been identified as the splice variant of the nNOS. While there is still some conjecture about the existence of mtNOS, both mitochondria and submitochondrial preparations have been shown to yield rates of 0.25-0.90 nmol NO min-1 mg protein-1 . The importance of this is critical as the reaction between O- and nitric oxide (NO) yields peroxynitrite (ONOO-).
The intramitochondrial metabolites, O-, H2O2, NO, and ONOO], are prooxi-dants, potentially leading to oxidative stress and damage. Two of them, O- and NO, are free radicals; however, are considered less reactive and do not participate in destructive propagation reactions, although they do participate in termination reactions yielding H2O2 and ONOO-. The latter two species are potentially harmful due to the potential to generate the reactive hydroxyl radical.
While the mitochondrial ETC is capable of ROS production under normal physiological conditions, mitochondrial dysfunction can result in an increase in ROS production and has been implicated in numerous pathological conditions including Alzheimer's disease  and ischemia , In most cases of pathological mitochondrial dysfunction, elevated oxidative damage is thought to play a role [36-40]. This is because the mitochondrion is a major source of the ROS within the cell that leads to oxidative damage [41, 42]. As mitochondria are particularly susceptible to oxidative damage, this contributes to mitochondrial dysfunction and cell death in a range of diseases. Due to the susceptible nature of mitochondrial DNA (mtDNA) in comparison to nuclear DNA, a negative loop can develop wherein excessive mito-chondrial ROS generation leads to oxidative damage to the mtDNA. This is turn has been shown to cause mitochondrial dysfunction which further exacerbates or initiates mitochondrial ROS production, thus creating an increasing cycle of mitochondrial dysfunction and oxidative stress.
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