**4. Mitochondria, cell injury, and apoptosis**

Manganese superoxide dismutase (MnSOD) and glutathione represent endogenous molecules that minimize mitochondrial-derived ROS. Mitochondrial injury occurs, however, when ROS formation exceeds the capacity for their removal by these antioxidant mechanisms. ROS biochemically modify other molecules to produce cytotoxic species that induce cellular injury [28]. For example, ROS induce the formation of 4-hydroxynonenal (HNE), a reactive lipid species that is associated with neuronal damage in brains of Parkinson's disease patients [29, 30]. ROS production also leads to cell death *via* the induction of apoptosis. Activation of the intrinsic apoptotic pathway occurs in response to a decrease in mitochondrial membrane potential, opening of the mPTP and release of cytochrome C [23]. Cytochrome C initiates the pro-apoptotic cascade by activating the initiator caspase 9, which in turn cleaves the final effector caspase 3. There are also a number of proteins that regulate apoptosis, including anti-apoptotic Bcl-2, and pro-apoptotic *Bax* and *Bad* proteins [31]. When cytosolic *Bax* binds to the outer mitochondrial membrane, it induces apoptosis by stimulating cytochrome C release. Further, the binding of *Bax* to Bcl-2 inhibits the antiapoptotic effects of Bcl-2, resulting in cell death. The dimerization and localization of this group of proteins modulate apoptosis under both basal and pathological conditions and can be modified by the cellular microenvironment.
