RESUMO
There is increasing evidence that inducing neuronal mitophagy can be used as a therapeutic intervention for Alzheimer's disease. Here, we screen a library of 2024 FDA-approved drugs or drug candidates, revealing UMI-77 as an unexpected mitophagy activator. UMI-77 is an established BH3-mimetic for MCL-1 and was developed to induce apoptosis in cancer cells. We found that at sub-lethal doses, UMI-77 potently induces mitophagy, independent of apoptosis. Our mechanistic studies discovered that MCL-1 is a mitophagy receptor and directly binds to LC3A. Finally, we found that UMI-77 can induce mitophagy in vivo and that it effectively reverses molecular and behavioral phenotypes in the APP/PS1 mouse model of Alzheimer's disease. Our findings shed light on the mechanisms of mitophagy, reveal that MCL-1 is a mitophagy receptor that can be targeted to induce mitophagy, and identify MCL-1 as a drug target for therapeutic intervention in Alzheimer's disease.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Mitofagia/efeitos dos fármacos , Mitofagia/fisiologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/efeitos dos fármacos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteína 5 Relacionada à Autofagia/economia , Sobrevivência Celular , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Glucose , Células HEK293 , Células HeLa , Ensaios de Triagem em Larga Escala , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteínas de Neoplasias , Proteínas do Tecido Nervoso , Neurônios/metabolismo , Oxigênio , Receptores Citoplasmáticos e Nucleares , Sulfonamidas/farmacologia , Tioglicolatos/farmacologiaRESUMO
Hierarchical SAPO-34 catalysts with abundant intracrystalline mesopores have been prepared using morpholine as the template combined with a cheap nonsurfactant cationic surfactant. Significantly, the hierarchical SAPO-34 catalysts exhibit more than 5-fold improved lifetime and 12% enhanced selectivity for ethylene and propylene compared to conventional microporous counterparts in methanol-to-olefin (MTO) reactions.