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El estrés apoptótico causa la liberación de ADNmt durante la senescencia y impulsa el SASP
Stella Victorelli1,2, Hanna Salmonowicz1,2,3,4, James Chapman3
1Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
Nature
|October 11, 2023
Resumen
La senescencia celular desencadena la disfunción relacionada con la edad a través del fenotipo secretor asociado a la senescencia (SASP). La inhibición de la permeabilización de la membrana externa mitocondrial (MOMP) en las células senescentes reduce la inflamación y extiende la vida útil en ratones.
Área de la Ciencia:
- Biología celular
- Investigación sobre el envejecimiento
- Biología mitocondrial
Sus antecedentes:
- Las células senescentes contribuyen a la disfunción tisular relacionada con la edad a través del fenotipo secretor asociado a la senescencia (SASP).
- Las mitocondrias regulan el SASP, pero los mecanismos precisos siguen sin estar claros.
- La permeabilización de la membrana externa mitocondrial (MOMP) es un evento clave en la apoptosis, distinto de la senescencia.
Objetivo del estudio:
- Para investigar el papel de las mitocondrias en la senescencia celular y SASP.
- Para aclarar los mecanismos que vinculan la dinámica mitocondrial con la inducción de SASP.
- Explorar estrategias terapéuticas dirigidas a las vías mitocondriales en el envejecimiento.
Principales métodos:
- Caracterización de la permeabilización de la membrana externa mitocondrial (MOMP) en las células senescentes.
- Análisis de las funciones de BAX y BAK en la MOMP minoritaria (miMOMP).
- Evaluación de la liberación de ADN mitocondrial (mtDNA) y la activación de la vía cGAS-STING.
- Estudios in vivo en ratones envejecidos para evaluar el impacto de la inhibición de la MOMP en la inflamación y la salud.
Principales resultados:
- La permeabilización de la membrana externa mitocondrial (MOMP) en un subconjunto de mitocondrias (MOMP minoritaria o miMOMP) se identifica como una característica de la senescencia celular.
- El miMOMP requiere BAX y BAK, lo que lleva a la liberación de ADN mitocondrial (ADNmt) en el citosol.
- El mtDNA citosólico activa la vía cGAS-STING, un regulador crítico del SASP.
- La inhibición de la MOMP in vivo redujo los marcadores inflamatorios y mejoró la esperanza de vida en ratones envejecidos.
Conclusiones:
- La senescencia celular y la apoptosis comparten mecanismos regulatorios dependientes de las mitocondrias.
- El estrés apoptótico subletal mitocondrial, específicamente miMOMP, es un factor importante del SASP.
- La inhibición de la inflamación inducida por miMOMP presenta una estrategia terapéutica potencial para mejorar la salud en el envejecimiento.
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