Discovery of Mitophagy Inhibitors with Therapeutic Potential in Different Familial Amyotrophic Lateral Sclerosis Mutations.
Ines MaestroLaura Rodriguez de la BallinaGracia PorrasSilvia CorrochanoEva de LagoAnne SimonsenPatricia BoyaAna MartinezPublished in: International journal of molecular sciences (2022)
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 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 identified a new mitophagy inhibitor, the small molecule named IGS2.7 from the MBC library. Interestingly, the treatment of different cellular and in vivo models of ALS with mutations on SOD1 and TARDBP with this inhibitor restores autophagy to control levels. These results point mitophagy inhibitors, especially IGS2.7, to a new therapeutic approach for familial ALS patients.
Keyphrases
- amyotrophic lateral sclerosis
- cell death
- small molecule
- end stage renal disease
- nlrp inflammasome
- ejection fraction
- oxidative stress
- chronic kidney disease
- newly diagnosed
- signaling pathway
- endoplasmic reticulum stress
- prognostic factors
- peritoneal dialysis
- high throughput
- early onset
- reactive oxygen species
- patient reported outcomes
- bone mineral density
- body composition
- single cell