Small molecule agonist of mitochondrial fusion repairs mitochondrial dysfunction.
Nat Chem Biol
; 19(4): 468-477, 2023 04.
Article
em En
| MEDLINE
| ID: mdl-36635564
ABSTRACT
Membrane dynamics are important to the integrity and function of mitochondria. Defective mitochondrial fusion underlies the pathogenesis of multiple diseases. The ability to target fusion highlights the potential to fight life-threatening conditions. Here we report a small molecule agonist, S89, that specifically promotes mitochondrial fusion by targeting endogenous MFN1. S89 interacts directly with a loop region in the helix bundle 2 domain of MFN1 to stimulate GTP hydrolysis and vesicle fusion. GTP loading or competition by S89 dislodges the loop from the GTPase domain and unlocks the molecule. S89 restores mitochondrial and cellular defects caused by mitochondrial DNA mutations, oxidative stress inducer paraquat, ferroptosis inducer RSL3 or CMT2A-causing mutations by boosting endogenous MFN1. Strikingly, S89 effectively eliminates ischemia/reperfusion (I/R)-induced mitochondrial damage and protects mouse heart from I/R injury. These results reveal the priming mechanism for MFNs and provide a therapeutic strategy for mitochondrial diseases when additional mitochondrial fusion is beneficial.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Transporte da Membrana Mitocondrial
/
Dinâmica Mitocondrial
Limite:
Animals
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article