Patients with ALS show, in addition to the loss of motor neurons in the spinal cord, brainstem, and cerebral cortex, an abnormal depletion of energy stores alongside hypermetabolism. In this study, we show that bioenergetic defects and muscle remodeling occur in skeletal muscle of the SOD1^G93A mouse model of ALS mice prior to disease onset and before the activation of muscle denervation markers, respectively. These changes in muscle physiology were followed by an increase in energy expenditure unrelated to physical activity. Finally, chronic treatment of SOD1^G93A mice with Ranolazine, an FDA-approved inhibitor of fatty acid β-oxidation, led to a decrease in energy expenditure in symptomatic SOD1^G93A mice, and this occurred in parallel with a robust, albeit temporary, recovery of the pathological phenotype.

Vulnerability of motoneurons in amyotrophic lateral sclerosis (ALS) arises from a combination of several mechanisms, including protein misfolding and aggregation, mitochondrial dysfunction and oxidative damage. Protein aggregates are found in motoneurons in models for ALS linked to a mutation in the gene coding for Cu,Zn superoxide dismutase (SOD1) and in ALS patients as well. Aggregation of mutant SOD1 in the cytoplasm and/or into mitochondria has been repeatedly proposed as a main culprit for the degeneration of motoneurons. It is, however, still debated whether SOD1 aggregates represent a cause, a correlate or a consequence of processes leading to cell death. We have exploited the ability of glutaredoxins (Grxs) to reduce mixed disulfides to protein thiols either in the cytoplasm and in the IMS (Grx1) or in the mitochondrial matrix (Grx2) as a tool for restoring a correct redox environment and preventing the aggregation of mutant SOD1. Here we show that the overexpression of Grx1 increases the solubility of mutant SOD1 in the cytosol but does not inhibit mitochondrial damage and apoptosis induced by mutant SOD1 in neuronal cells (SH-SY5Y) or in immortalized motoneurons (NSC-34). Conversely, the overexpression of Grx2 increases the solubility of mutant SOD1 in mitochondria, interferes with mitochondrial fragmentation by modifying the expression pattern of proteins involved in mitochondrial dynamics, preserves mitochondrial function and strongly protects neuronal cells from apoptosis. The toxicity of mutant SOD1, therefore, mostly arises from mitochondrial dysfunction and rescue of mitochondrial damage may represent a promising therapeutic strategy.

It is well known that mitochondrial damage is both the major contributor to oxidative stress (the condition arising from unbalance between production and removal of reactive oxygen species) and one of the major consequences of oxidative stress, because of the high dependence of mitochondrial function on redox-sensitive targets such as intact membranes. Conditions in which neuronal cells are not able to cope with mitochondrial damage and oxidative stress seem to lead or contribute to several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS), at least in the most studied SOD1-linked genetic variant. As summarized in this review, new evidence indicates that mitochondrial damage and oxidative stress play a role also in non-SOD1 ALS and thus they may represent a target for therapy despite previous failures in clinical trials.