**4. Mutant SOD1 translocation to mitochondria**

Mitochondria are one of the major sources of cellular ROS formed as by-products of oxidative phosphorylation. Abnormalities in the mitochondrial structure, localization and number as well as altered activity of the electron transport chain have been described in both, sporadic and familial ALS (Manfredi and Xu, 2005). The mitochondrial electron transport chain and ATP synthesis are severely impaired at disease onset in spinal cord and brain of SOD1G93A transgenic mice (Lin and Beal, 2006). Both, wild type and mutant SOD localize in mitochondria in the central nervous system (Higgins et al., 2002). Mutant human SOD1 was found in the mitochondrial outer membrane, intermembrane space and matrix in transgenic mice, while inactive mutant SOD1 accumulates and forms aggregates in the mitochondrial matrix in the brain (Vijayvergiya et al., 2005). Aggregates of the mutant enzyme are also selectively found in the mitochondrial outer membrane in spinal cord from mouse models of ALS (Liu et al., 2004). Interestingly, the anti-apoptotic protein Bcl-2 binds to mutant SOD1 and aggregates in spinal cord mitochondria from patients and a mouse model of ALS, suggesting that mutant SOD1 may be toxic by depleting motor neurons of this anti-apoptotic protein (Pasinelli et al., 2004). Mutant SOD1 targeted to the mitochondrial intermembrane space in NSC34 cells induces cell death upon exposure of the cells to hydrogen peroxide (Magrane et al., 2009). In addition, the increase in carbonylated proteins and lipid hydroperoxides in mitochondria, as well as the abnormally high rates of production of hydrogen peroxide in SOD1G93A transgenic mice (Mattiazzi et al., 2002; Panov et al., 2011) support the mutant SOD1 aberrant catalytic gain-of-function. Indeed, it was shown that metal-deficient SOD1s are prone to mitochondrial translocation and are found in the mitochondrial intermembrane space (Okado-Matsumoto and Fridovich, 2002). The mitochondria contain the majority of the cellular copper because is required by the oxygen-consuming proteins. The insertion of copper into the translocated metal-deficient SOD would result in the formation of Zn-deficient SOD inside the mitochon‐ dria (Figure 1A). This could explain why the mitochondria are affected early in the onset of the disease (Beckman et al., 2002). The ROS-linked toxic gain-of-function of mutant SOD1 would produce hydroxyl radical from H2O2 as well as peroxynitrite in the mitochondria. The mutant enzyme could then catalyze the nitration of mitochondrial proteins such as cyclophilin D and the adenine nucleotide translocator (Martin, 2010). Due to these toxic effects of mutant SOD1 on mitochondria, it has been proposed that the abnormal activity of the mitochondria in ALS may account for the initiation and progression of the disease. However, whether the mitochondrial localization of mutant SOD1 is cause or a consequence of pathology needs to be established.
