Los macroporos BAK/BAX facilitan la hernia mitocondrial y el eflujo de ADNmt durante la apoptosis
Kate McArthur1,2,3, Lachlan W Whitehead4,2, John M Heddleston5
1Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. kate.mcarthur@monash.edu benjamin.kile@monash.edu.
Science (New York, N.Y.)
|February 24, 2018
Resumen
Las células moribundas liberan ADN mitocondrial (ADNmt) para desencadenar la inmunidad innata a través de la vía cGAS/STING. Los poros BAK / BAX permiten la hernia de la membrana mitocondrial interna, exponiendo el ADNmt y activando la señalización del interferón de tipo I.
Área de la Ciencia:
- Biología celular
- Inmunología
- Biología molecular
Sus antecedentes:
- La permeabilización de la membrana externa mitocondrial (MOMP) por las proteínas BAK y BAX inicia la apoptosis.
- Las células moribundas que carecen de caspasas activas pueden activar la vía inmune innata cGAS / STING a través del ADN mitocondrial (mtDNA).
- El mecanismo por el cual el mtDNA accede a los sensores citosólicos como el cGAS no se comprende completamente.
Objetivo del estudio:
- Para investigar cómo el ADN mitocondrial (ADNmt) obtiene acceso al citosol durante la apoptosis.
- Para aclarar el papel de los poros BAK / BAX en la liberación de ADNmt y la activación inmune innata.
Principales métodos:
- Se empleó microscopía de lámina de celda viva para visualizar la dinámica de la red mitocondrial en fibroblastos embrionarios de ratón.
- El estudio se centró en las células sometidas a apoptosis mediada por BAK/ BAX con pérdida de citocromo c.
Principales resultados:
- La activación de BAK/BAX condujo a la ruptura de la red mitocondrial y la formación de grandes poros en la membrana mitocondrial externa.
- Estos macroporos BAK / BAX facilitaron la herniación de la membrana mitocondrial interna en el citosol.
- La hernia entregó el contenido de la matriz mitocondrial, incluido el ADNmt, al citosol, lo que permitió la activación de la vía cGAS/STING.
- Se observó que las caspasas activas desmantelaron la célula, suprimiendo potencialmente la señalización inmune inducida por el ADNmt.
Conclusiones:
- Los macroporos mediados por BAK/BAX son cruciales para la hernia de la membrana mitocondrial interna y la liberación citosólica de ADNmt durante la apoptosis.
- Este mecanismo de herniación explica cómo el ADNmt accede a los sensores inmunes innatos citosólicos.
- El desmantelamiento celular por caspases puede servir para limitar la inflamación desencadenada por el ADN.
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