More than 90% of ATP generation in the CNS occurs via mitochondrial oxidative phosphorylation (Hyder et al., 2013; Vandoorne et al., 2018). Reductions in energy metabolism have been reported in ALS (Vandoorne et al., 2018) and mitochondrial abnormalities, such as swelling and morphological changes, are among the earliest signs of pathology in SOD1G93A and SOD1G37R mice (Wong et al., 1995; Kong and Xu, 1998), FUSR521C rats (Huang et al., 2012; So et al., 2018) and wild type TDP-43 mice (Shan et al., 2010; Xu et al., 2010). Moreover, mitochondrial abnormalities are also present in MNs of ALS patient tissues (Fujita et al., 1996; Sasaki and Iwata, 1996; Swerdlow et al., 1998; Dhaliwal and Grewal, 2000; Sasaki et al., 2007). Furthermore, mutant SOD1 specifically associates with mitochondria and interferes with their function (Liu et al., 2004; Pasinelli et al., 2004; Ferri et al., 2006; Sotelo-Silveira et al., 2009; Vande Velde et al., 2011). Decreased activity of mitochondrial respiratory chain complexes was also present in spinal cord sections (Borthwick et al., 1999) and homogenates (Wiedemann et al., 2002) from ALS patients. Consistent with these findings, genes involved in mitochondrial function were upregulated in rat oculomotor neurons compared to hypoglossal and cervical spinal cord MNs. However, it should be noted that the higher firing rate of the former might confer some resistance to energy imbalance (Hedlund et al., 2010; Brockington et al., 2013).