**11. Conclusions**

The results presented by us in this and other papers (Panov et al., 2009, 20011a, 2011b) lead us to suggest the role of the brain and spinal cord mitochondria in the loss of motor neurons in ALS. We hypothesize that increased oxidative stress associated with specific metabolic phenotypes, which promote reverse electron transport due to reduction of the membrane pool of ubiquinone by succinate (Panov et al., 2009, 2011a, 2011b) or fatty acids (Panov et al., 2010c), is a prerequisite for cases of sporadic ALS. The energy-dependent reverse electron transport is a way of dissipation of the mitochondrial membrane potential, which increases the rate of resting mitochondrial respiration. In mammals, the standard metabolic rate depends on the intrinsic (in state 4) mitochondrial proton conductivity (Rolfe & Brown , 1997). Therefore in patients with ALS hypermetabolism could be associated with the systemically increased dissipation of mitochondrial membrane potential. The specific vulnerability of motor neurons in ALS is, more likely than not, associated with the specific features of spinal cord described in Panov et al. (2011a, 2011b).

Normally, SCM produce significantly more ROS than BM when oxidizing physiologically relevant mixture of neuromediator glutamate and the tricarboxylic acid cycle substrates pyruvate, succinate and malate. Mutated SOD1 is extremely sensitive to the damaging effect of H2O2, which in tgBM and tgSCM were dramatically increased. This results in demetallation of mSOD1 and association with mitochondria, thus changing the physical properties of the mitochondrial membranes and further enhancing production of ROS. Increased oxidative stress initiates damage to myelin and released the tissue calcium. Finally, oxidatively damaged mitochondria undergo the Ca2+-induced permeability transition, and motor neurons die by apoptotic or necrotic pathway. Thus, mitochondria are early and directly involved in the pathogenesis of ALS. We suggest that sporadic ALS is preferentially acquired by individuals with the mitochondrial metabolic phenotype, that promotes very high levels of ROS production. In individuals with mutated SOD1 gene, the abnormal SOD1 protein has high sensitivity to deleterious effect of H2O2 and the disease may develop even at normal levels of ROS production.
