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Published on: October 5, 2012
Mitochondrial ceramide-rich macrodomains functionalize Bax upon irradiation
Hyunmi Lee1, Jimmy A Rotolo, Judith Mesicek
1Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
Plos One
|June 23, 2011
Summary
Mitochondrial ceramide elevation forms a novel platform, the MCRM, which facilitates Bax insertion and pore formation, driving apoptosis. This discovery offers new therapeutic targets for managing cell death pathways.
Area of Science:
- Cell Biology
- Biochemistry
- Apoptosis Research
Background:
- Bax protein acts as a "lipidic" pore, crucial for mitochondrial outer membrane permeabilization (MOMP) during apoptosis.
- The precise membrane elements facilitating Bax function in MOMP remained largely unknown.
Purpose of the Study:
- To elucidate the mechanism by which mitochondrial ceramide facilitates MOMP and cytochrome c release.
- To identify and characterize novel membrane structures involved in Bax-mediated apoptosis.
Main Methods:
- Utilized confocal microscopy to visualize mitochondrial ceramide-rich macrodomains (MCRMs) in HeLa cells.
- Isolated MCRMs biophysically and analyzed Bax integration and oligomerization.
- Employed Fumonisin B1, a ceramide synthase inhibitor, to assess the role of ceramide generation in MOMP.
- Investigated Bax oligomerization states within MCRMs using purified mitochondria.
Main Results:
- MCRMs form upon irradiation and ceramide elevation, promoting Bax insertion, oligomerization, and MOMP.
- Inhibition of ceramide generation blocked radiation-induced Bax insertion, oligomerization, and MOMP.
- Bax integrates into MCRMs, forming pore-like structures that enhance cytochrome c release.
- Monomeric Bax was found in non-MCRM membranes, while MCRM-associated Bax formed high molecular weight oligomers.
Conclusions:
- Mitochondrial ceramide generation creates a platform (MCRM) essential for Bax-mediated MOMP in mammalian cells.
- Ceramide acts as a stress calibrator, organizing membrane domains to regulate the intensity of Bax-induced apoptosis.
- The MCRM-Bax interaction represents a pharmacologically tractable target for modulating apoptosis.
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