@article{463c82b3c52b4a5894ba7993978e40a1,
title = "Sphingolipid metabolism cooperates with BAK and BAX to promote the mitochondrial pathway of apoptosis",
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.",
author = "Chipuk, {Jerry E.} and McStay, {Gavin P.} and Archana Bharti and Tomomi Kuwana and Clarke, {Christopher J.} and Siskind, {Leah J.} and Obeid, {Lina M.} and Green, {Douglas R.}",
note = "Funding Information: We would like to thank Dr. Ronald Gordon (MSSM) for TEM analysis; Dr. Richard Kolesnick (Memorial Sloan-Kettering) for the asm −/− liver; Dr. Joseph Opferman (SJCRH) for the MxCre bak −/− bax -/f animals; all members of the Obeid and Hannun laboratories (MUSC) for excellent discussion and training in sphingolipid biology, especially Drs. K. Alexa Orr Gandy, Stefka Spassieva, and Xingjun Wu; The Hartwell Center for Bioinformatics and Biotechnology; and members of the Kuwana Laboratory for technical assistance. This work was supported by: NIH CA157740 (to J.E.C.), pilot project from NIH P20AA017067 (to J.E.C.), NIH AI52735 (to D.R.G.), CA69381 (to D.R.G.), NIH AG024478 (to T.K.), an NCI Cancer Center Core Grant P30CA21765 (SJCRH), VA Merit (to L.M.O.), VA CDA-2 Award (to L.J.S), pilot project from the VA REAP (to L.J.S., and L.M.O.), the ACS IRG #IRG-97-219-11 (subaward to L.J.S.), Lipidomics Shared Resource of the Hollings Cancer Center supported by a Cancer Center Support Grant (P30 CA138313), pilot project (to L.J.S) from the NIH/NCRR P20 RR17677 COBRE in Lipidomics and Pathobiology, and the American Lebanese Syrian Associated Charities. This work was also supported in part by a Research Grant 5-FY11-74 from the March of Dimes Foundation (to J.E.C.). ",
year = "2012",
month = mar,
day = "2",
doi = "10.1016/j.cell.2012.01.038",
language = "English",
volume = "148",
pages = "988--1000",
journal = "Cell",
issn = "0092-8674",
publisher = "Elsevier B.V.",
number = "5",
}