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El estrés mitocondrial se transmite al citosol por una vía OMA1-DELE1-HRI
Xiaoyan Guo1,2, Giovanni Aviles1,2, Yi Liu3
1Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, USA.
Nature
|March 6, 2020
Resumen
El estrés mitocondrial activa la vía OMA1-DELE1-HRI, transmitiendo señales para inducir ATF4 a través de la fosforilación eIF2α. Esta vía es crucial para la respuesta integrada al estrés en las células de mamíferos.
Área de la Ciencia:
- Biología celular
- Mecanismos moleculares de la respuesta al estrés
Sus antecedentes:
- La disfunción mitocondrial activa la respuesta integrada al estrés (ISR) en las células de los mamíferos.
- La fosforilación del factor de iniciación de la traducción eucariota 2α (eIF2α) conduce a la inducción de ATF4 durante la ISR.
- El mecanismo preciso que transmite el estrés mitocondrial al ATF4 sigue siendo elusivo.
Objetivo del estudio:
- Para identificar la vía de señalización que transmite el estrés mitocondrial a la inducción de ATF4.
- Para aclarar las funciones de HRI, OMA1 y DELE1 en esta vía de respuesta al estrés.
Principales métodos:
- Evaluación de la interferencia CRISPR en todo el genoma para identificar los factores anteriores.
- Ensayos bioquímicos para estudiar las interacciones de las proteínas y la actividad de la quinasa.
- Análisis de la traducción de ATF4 y activación de la respuesta integrada al estrés.
Principales resultados:
- HRI (inhibidor regulado por el hemo) fue identificado como la eIF2α quinasa esencial para la transmisión del estrés mitocondrial.
- OMA1 (una proteasa) y DELE1 (una proteína mitocondrial) funcionan aguas arriba de HRI.
- El estrés mitocondrial desencadena la escisión DELE1 dependiente de OMA1, lo que lleva a la acumulación de DELE1 citosólico y la activación de HRI.
- DELE1 es esencial para la traducción ATF4 aguas abajo de la fosforilación de eIF2α.
- La inhibición de la vía OMA1-DELE1-HRI induce una respuesta de acompañamiento alternativa.
Conclusiones:
- La vía OMA1-DELE1-HRI es el relevo primario para el estrés mitocondrial al ATF4.
- Esta vía representa un objetivo terapéutico potencial para la modulación de la ISR en enfermedades asociadas con la disfunción mitocondrial.
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