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Monitoring Dynamic Changes In Mitochondrial Calcium Levels During Apoptosis Using A Genetically Encoded Calcium Sensor
Published on: April 1, 2011
La regulación BAX y BAK del retículo endoplasmático Ca2+: un punto de control para la apoptosis
Luca Scorrano1, Scott A Oakes, Joseph T Opferman
1Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Department of Pathology and Medicine, Harvard Medical School, Boston, MA 02115, USA.
Science (New York, N.Y.)
|March 8, 2003
Resumen
Las proteínas proapoptóticas BAX y BAK son cruciales para iniciar la apoptosis mediante la regulación de los niveles de calcio en el retículo endoplasmático (ER) y las mitocondrias. Su presencia es esencial para las vías específicas de muerte celular.
Área de la Ciencia:
- Biología celular Biología celular.
- Biología Molecular Biología Molecular
- La bioquímica es la bioquímica.
Sus antecedentes:
- BAX y BAK son proteínas proapoptóticas clave involucradas en el inicio de la disfunción mitocondrial.
- Estas proteínas también se localizan en el retículo endoplasmático (RE), lo que sugiere un papel más allá de las mitocondrias.
Objetivo del estudio:
- Investigar el papel de BAX y BAK en la regulación de la homeostasis del calcio ER y su impacto en la apoptosis.
- Determinar cómo la localización de BAX y BAK afecta la sensibilidad a diferentes estímulos apoptóticos.
Principales métodos:
- Se utilizaron fibroblastos embrionarios de ratón con deficiencia de BAX y BAK (células DKO).
- Se evaluaron las concentraciones de calcio ER ([Ca2+]er) y la absorción de calcio mitocondrial.
- Expresión SERCA restaurada para corregir la desregulación del calcio.
- Investigó la inducción de la apoptosis utilizando varios agentes, incluidos los que liberan calcio de las reservas intracelulares y las señales solo de BH3.
- Examinó el requisito para la liberación de calcio ER y mitocondrial BAX / BAK para la apoptosis.
Principales resultados:
- Las células DKO exhibieron una reducción del [Ca2+]er en reposo y una disminución de la absorción de calcio mitocondrial.
- La expresión de SERCA restauró el [Ca2+]er y la absorción de calcio mitocondrial, re-sensibilizando las células DKO a ciertos estímulos apoptóticos.
- Dirigir BAX a las mitocondrias restauró la apoptosis solo a las señales BH3-sólo.
- Muchas señales apoptóticas intrínsecas requerían tanto la liberación de calcio ER como el BAX/BAK. mitocondrial.
Conclusiones:
- BAX y BAK actúan como pasarelas esenciales para señales apoptóticas específicas tanto en el ER como en las mitocondrias.
- La regulación del calcio ER por BAX y BAK es crítica para iniciar la apoptosis en respuesta a ciertas tensiones celulares.
- La localización de BAX y BAK dicta su papel en la mediación de distintas vías apoptóticas.
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