Targeting Mitochondrial Fission Produces Both Neuroprotective and Detrimental Effects in the SOD1 Mouse Model of Amyotrophic Lateral Sclerosis

Abstract

Simple Summary Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, leading to progressive muscle weakness and severe muscle wasting. In addition to neuronal loss, increasing evidence suggests that problems in mitochondrial function, the process by which cells produce energy, may contribute to disease development and progression. In this study, we investigated the effects of Mdivi-1, a drug that inhibits mitochondrial fragmentation, in a mouse model of ALS. Treatment began before symptoms appeared in order to assess whether it could slow disease progression. Our findings showed that Mdivi-1 partially protected motor neurones in the spinal cord, but this did not result in improved motor performance. Moreover, treated animals developed more severe muscle wasting and changes in muscle fiber composition. We also observed cellular alterations associated with impaired neuromuscular function. Overall, these results highlight that mitochondrial dynamics play a complex and context-dependent role in the disease. A better understanding of these mechanisms will be important for developing more effective therapeutic strategies for ALS.