Mitochondria exist in the cells as highly dynamic entities, ranging from elaborate tubular networks to small organelles, through rapid and opposing processes of fission and fusion. Mitochondrial fission, the focus of our study, is mediated by the recruitment of Drp1, a cytosolic large GTPase, to the outer mitochondrial membrane by mitochondrial fission factor (Mff), mitochondrial dynamics proteins of 49 kDa and 51 kDa (Mid49/Mid51) and through fission 1 (Fis1; Loson et al, 2013; Osellame et al, 2016). Whereas physiological fission is essential for maintaining mitochondrial quality (Shirihai et al, 2015), excessive Drp1‐mediated fission causes mitochondrial fragmentation, mitochondrial membrane depolarization, increase in reactive oxygen production (ROS) and oxidative stress, and a decrease in ATP production and in other mitochondrial functions (Wu et al, 2011; Youle & van der Bliek, 2012; Babbar & Sheikh, 2013). Indeed, we found that inhibition of excessive Drp1 activity through blocking its interaction with Fis1 is protective in models of Parkinson's disease and Huntington's disease (Guo et al, 2013; Qi et al, 2013). Here, we determined whether Drp1 hyperactivation plays a role in the pathogenesis of ALS and whether inhibition of Drp1 hyperactivation through its interaction with Fis1 can reduce ALS pathology.