Sphingolipid metabolism cooperates with BAK and BAX to promote the mitochondrial pathway of apoptosis.
Cell
; 148(5): 988-1000, 2012 Mar 02.
Article
em En
| MEDLINE
| ID: mdl-22385963
ABSTRACT
Mitochondria are functionally and physically associated with heterotypic membranes, yet little is known about how these interactions impact mitochondrial outer-membrane permeabilization (MOMP) and apoptosis. We observed that dissociation of heterotypic membranes from mitochondria inhibited BAK/BAX-dependent cytochrome c (cyto c) release. Biochemical purification of neutral sphingomyelinases that correlated with MOMP sensitization suggested that sphingolipid metabolism coordinates BAK/BAX activation. Using purified lipids and enzymes, sensitivity to MOMP was achieved by in vitro reconstitution of the sphingolipid metabolic pathway. Sphingolipid metabolism inhibitors blocked MOMP from heavy membrane preparations but failed to influence MOMP in the presence of sphingolipid-reconstituted, purified mitochondria. Furthermore, the sphingolipid products, sphingosine-1-PO(4) and hexadecenal, cooperated specifically with BAK and BAX, respectively. Sphingolipid metabolism was also required for cellular responses to apoptosis. Our studies suggest that BAK/BAX activation and apoptosis are coordinated through BH3-only proteins and a specific lipid milieu that is maintained by heterotypic membrane-mitochondrial interactions.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Esfingolipídeos
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Apoptose
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Proteína X Associada a bcl-2
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Proteína Killer-Antagonista Homóloga a bcl-2
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Redes e Vias Metabólicas
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Mitocôndrias
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Cell
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos