**6. Mitochondrial deficiency and energy balance**

In motoneurons under normal conditions, the mitochondrial membrane potential powers both the Ca2+ uniporter and ATP synthase, so in periods of heavy Ca2+ influx, ATP production could be impaired (Mattson et al., 2008, Nguyen et al., 2009). The increased Ca2+ influx in SOD1 motoneurons is likely to further impair the function of mitochondria under these conditions. In addition, SOD1 mitochondria appear to be impaired in function under basal conditions (Mattiazzi et al., 2002, Nguyen et al., 2009, Li et al., 2010). Before the onset of symptoms, SOD1 mitochondria show decreased protein import, altered Ca2+ sequestering, and an exaggerated response of the electrical gradient of the inner membrane to stimulation-induced Ca2+ influx (Damiano et al., 2006, Bilsland et al., 2008, Jaiswal et al., 2009, Nguyen et al., 2009, Li et al., 2010). By the time symptoms appear there is severe damage to mitochondrial membrane potentials, respiration, the electron transport chain and ATP synthesis (Mattiazzi et al., 2002, Jaiswal and Keller, 2009). Another impairment is misfolded SOD1 binding to VDAC1, the general diffusion pore for anions and cations, including Ca2+. Both mitochondrial conductance and the uptake of ADP are thereby reduced, however, this is not observed until after the onset of symptoms (Israelson et al., 2010). Early alterations in SOD1 mitochondria must take place though another mechanism.

In summary, not only are there fewer mitochondria present in the processes of SOD1 neurons (De Vos et al., 2007, Bilsland et al., 2010), but those that are present are impaired in functioning. This is likely to have dire consequences for both Ca2+ buffering and ATP production in the large and metabolically-active SOD1 motoneurons.
