Sphingolipid metabolism cooperates with BAK and BAX to promote the mitochondrial pathway of apoptosis

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

Research output: Contribution to journalArticlepeer-review

349 Scopus citations

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-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.

Original languageEnglish
Pages (from-to)988-1000
Number of pages13
JournalCell
Volume148
Issue number5
DOIs
StatePublished - 2 Mar 2012

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