Details

Autor(en) / Beteiligte

• Chipuk, Jerry E.
• McStay, Gavin P.
• Bharti, Archana
• Kuwana, Tomomi
• Clarke, Christopher J.
• Siskind, Leah J.
• Obeid, Lina M.
• Green, Douglas R.

Titel

Sphingolipid Metabolism Cooperates with BAK and BAX to Promote the Mitochondrial Pathway of Apoptosis

Ist Teil von

• Cell, 2012-03, Vol.148 (5), p.988-1000

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2012

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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-PO4 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. [Display omitted] ► Mitochondria devoid of heterotypic membranes are resistant to cytochrome c release ► Mitochondrial sphingolipids promote BAK/BAX activation and cytochrome c release ► Sphingosine-1-PO4 and hexadecenal coordinate BAK and BAX activation, respectively ► Inhibition of sphingolipid metabolism blocks cytochrome c release and apoptosis Mitochondria require association with the intracellular membranes of other organelles to achieve the outer-membrane permeabilization that leads to apoptosis. This association is critical because sphingolipids generated by enzymes in these nonmitochondrial membranes activate the key cell death effector BAK and BAX.