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La granzima A divide una proteína del complejo I mitocondrial para iniciar la muerte celular independiente de la
Denis Martinvalet1, Derek M Dykxhoorn, Roger Ferrini
1Immune Disease Institute and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Cell
|May 20, 2008
Resumen
La granzima A (GzmA) de la proteasa linfocítica asesina induce la muerte celular al dirigirse al complejo mitocondrial I. GzmA divide NDUFS3, interrumpiendo la función y generando ROS, crítico para la muerte celular.
Área de la Ciencia:
- Inmunología Inmunología.
- Biología celular Biología celular.
- La bioquímica es la bioquímica.
Sus antecedentes:
- La granzima A (GzmA) es una proteasa citotóxica liberada por los linfocitos asesinos.
- GzmA induce la muerte celular independiente de la caspasa con características apoptóticas.
- Estudios anteriores indicaron que GzmA se dirige a las mitocondrias, generando especies reactivas de oxígeno (ROS) y alterando el potencial de la membrana mitocondrial, pero no la permeabilización de la membrana externa.
Objetivo del estudio:
- Para aclarar el mecanismo preciso por el cual GzmA induce el daño mitocondrial y la muerte celular.
- Para identificar el objetivo mitocondrial específico de GzmA.
- Para investigar el papel del complejo mitocondrial I en la citotoxicidad mediada por GzmA.
Principales métodos:
- Aislamiento mitocondrial y ensayos bioquímicos.
- Espectrometría de masas para identificar objetivos de escisión de GzmA.
- Mutagénesis dirigida al sitio de NDUFS3.
- Ensayos de viabilidad celular en respuesta al tratamiento con GzmA.
Principales resultados:
- GzmA tiene acceso directo a la matriz mitocondrial.
- GzmA divide la subunidad del complejo mitocondrial I NDUFS3 en Lys56.
- La escisión de NDUFS3 perjudica la oxidación de NADH y mejora la generación de aniones superóxido.
- Las células que expresan un sitio de escisión NDUFS3 mutado son resistentes a la muerte celular inducida por GzmA.
Conclusiones:
- La muerte celular mediada por GzmA depende de la escisión de la subunidad I del complejo mitocondrial NDUFS3.3.
- Este evento de escisión interrumpe la función mitocondrial, lo que lleva a la producción de ROS y a la citotoxicidad.
- La orientación de GzmA al complejo I proporciona un mecanismo específico para iniciar la muerte celular similar a la apoptosis.
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