Discovery of mitophagy inhibitors with therapeutic potential in different familiar Amyotrophic Lateral Sclerosis mutations

Abstract Mitophagy is the selective degradation of mitochondria by autophagy. It promotes the turnover of mitochondria and prevents the accumulation of dysfunctional mitochondria, which can lead to cellular degeneration. Mitophagy is known to be altered in several pathological conditions, especially in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We have recently demonstrated an increase in autophagy flux in lymphoblasts from ALS patients bearing a mutation in SOD1. Thus, the identification of mitophagy inhibitors may be a therapeutic option to recover mitochondrial homeostasis. Here, using a phenotypic mitophagy assay, we have identified a new mitophagy inhibitor, the small molecule named IGS2.7, from the MBC library. Interestingly, the treatment with this inhibitor of the different cellular and in vivo models of ALS with mutations on SOD1 and TARDBP, restores autophagy to control levels. These results point mitophagy inhibitors, specially IGS2.7, to a new therapeutic approach for familiar ALS patients.