Submitted on October 22, 2007
Revised on December 6, 2007
Accepted on December 11, 2007
Ceramide synthesis in the endoplasmic reticulum can permeabilize mitochondria to pro-apoptotic proteins
Johnny Stiban, Laura Caputo, and Marco Colombini
Biology, University of Maryland, College Park, MD 20742
Corresponding Author: colombini{at}umd.edu
Elevated mitochondrial ceramide levels are associated with the initiation of apoptosis. There is evidence that ceramide is causal. Thus the conversion of the precursor, dihydroceramide, to ceramide by the enzyme, dihydroceramide desaturase, may be important in preparing the cell for apoptosis. Ceramide can initiate apoptosis by permeabilizing the mitochondrial outer membrane to apoptosis-inducing proteins. However, the mitochondria’s ability to produce ceramide may be limited by its proteome. Here, we show that ceramide synthesized in isolated mammalian endoplasmic reticulum (ER) vesicles from either C8-dihydroceramide or sphingosine to produce long-chain ceramide, can transfer to isolated mitochondria. The rate of transfer is consistent with a simple collision model. The transfer of the long-chain ceramide is faster than expected for an uncatalyzed process. Sufficient ceramide is transferred to permeabilize the outer membrane to cytochrome c and adenylate kinase. The mitochondria associated membranes, ER-like membranes that are tightly-associated with isolated mitochondria, can produce enough ceramide to permeabilize the outer membrane transiently. Thus this ceramide exchange obviates the need for a complete ceramide de novo pathway in mitochondria in order to elevate ceramide levels to the critical value required for functional changes such as ceramide channel self-assembly followed by protein release.
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