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El reingreso de las células en reposo está limitado por el daño lisosomal inducido por la macroautofagia
Andrew Murley1, Ann Catherine Popovici1, Xiwen Sophie Hu1
1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
Cell
|April 9, 2025
Resumen
Las células quiescentes acumulan daño lisosómico debido a la macroautofagia dirigida a los agregados de proteínas. Limitar este daño al restringir la macroautofagia y estimular los lisosomas promueve la reactivación de las células en reposo, crucial para la reparación y el envejecimiento de los tejidos.
Área de la Ciencia:
- Biología celular
- Investigación sobre el envejecimiento
- Biología molecular
Sus antecedentes:
- La quiescencia celular es vital para la homeostasis de los tejidos, pero disminuye con el envejecimiento.
- La reactivación de las células en reposo se ve afectada en el envejecimiento, lo que afecta a la resiliencia del tejido.
- Los reguladores de la respuesta proteica desplegada (UPR) IRE-1 y XBP-1 son esenciales para la reactivación de las células en reposo.
Objetivo del estudio:
- Investigar los mecanismos subyacentes al daño de los lisosomas en las células en reposo.
- Identificar los factores que regulan la reparación de los lisosomas dañados en las células en reposo.
- Explorar estrategias para mejorar la reactivación celular en reposo.
Principales métodos:
- Examen genético avanzado en C. elegans para identificar los genes involucrados en el daño del lisosoma.
- Utilizó la inhibición de la macroautofagia y la estimulación del lisosoma (sobreexpresión de HLH-30) en C. elegans.
- Se ha investigado la orientación del agregado proteico hacia los lisosomas en células de mamíferos en reposo.
Principales resultados:
- La macroautofagia dirige los agregados de proteínas a los lisosomas en las células en reposo, causando daños.
- La inhibición genética de la macroautofagia y la sobreexpresión de HLH-30 redujeron sinérgicamente el daño de los lisosomas.
- Los lisosomas dañados requieren IRE-1/XBP-1 para su reparación después de una quiescencia prolongada.
- El daño de los lisosomas por los agregados de proteínas se produce en las células de mamíferos en reposo.
Conclusiones:
- El daño de los lisosomas es una característica de las células en reposo.
- La restricción de la macroautofagia y la estimulación de los lisosomas pueden mitigar el daño de los lisosomas.
- La reducción del daño de los lisosomas es una estrategia potencial para promover la reactivación celular en reposo y mejorar la homeostasis de los tejidos durante el envejecimiento.
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