**9. Proposed mechanisms of increased ROS production in tgSOD1 mitochondria**

There is strong evidence that tgSOD1 selectively binds to the outer (Vande Velde et al., 2008) and inner mitochondrial membranes (Liu et al., 2004; Ahtoniemi et al., 2008). Mutant SOD1 protein associated with mitochondria forms cross-linked oligomers and causes a shift in the redox state of respiratory components (Ferri et al., 2006). We propose a mechanism by which tgSOD1 might increase generation of ROS associated with reverse electron transport. The hypothesis is based on our recently published data on the effects of cholesterol β-Dglucoside and cycad phytosterol glucosides on ROS generation by BM (Panov et al., 2010b). These compounds are neurotoxic and suspected as the cause of the cluster of neurodegenerative disorders in the western Pacific termed amyotrophic lateral sclerosis– parkinsonism dementia complex (ALS-PDC) (Wilson et al., 2002). When added *in vitro* to mitochondria, cholesterol β-D-glucoside increased ROS production, which was specifically dependent on activity of SDH. Cholesterol β-D-glucoside is known to diminish the surface area of the membranes and thus affect the activity of the membrane's enzymes (Deliconstantinos et al., 1989). Here we suggest, that tgSOD1 upon its interaction with the mitochondria may change physical-chemical properties of the membranes and increase the rate of reverse electron transport in a way similar to that of cholesterol β-D-glucoside.
