Destabilizing the Mitochondrial Membrane

Abstract

Changes in phospholipid composition are part of the biochemical changes that occur during apoptosis. Cytochrome c is normally associated with the outer surface of the mitochondrial inner membrane by electrostatic forces. Changes in phospholipid composition may underlie the mechanism for release of cytochrome from the mitochondria in response to apoptotic stimuli. Bid is a proapoptotic member of the Bcl-2 family. Bid and its caspase-cleaved form, tBid, relocate to mitochondria in response to apoptotic signals, where Bid promotes release of cytochrome c, contributing to the apoptotic cascade. Esposti et al . found that Bid and tBid could stimulate the transfer of a fluorescent phospholipid analog to artificial membranes or mitochondrial membranes in an in vitro assay. Furthermore, the addition of lipids such as phosphatidylglycerol, phosphatidic acid, and phosphatidylcholine, but not phosphatidylserine, promoted the transfer of native Bid from subcellular fractions enriched in endoplasmic reticulum to mitochondria-enriched fractions. The authors suggest that under nonapoptotic conditions, Bid acts in phospholipid recycling. Under apoptotic conditions, internal membrane phospholipid composition is altered, such that during Bid's action as a lipid transfer protein, lipids are transferred to the mitochondria that destabilize the mitochondrial membrane, promoting cytochrome c release. Ostrander et al . investigated the changes in phospholipid composition that occur during apoptosis induced by treatment of cells with palmitic acid. Treatment of cells with this saturated long-chain fatty acid resulted in the accumulation of saturated phosphatid acid and phosphatidylglycerol, which are poor substrates for the biosynthetic enzymes that produce cardiolipin. Thus, cardiolipin levels drop, which may contribute to destabilization of the mitochondrial membrane based on the linear correlation of cardiolipin levels with cytochrome c released into the cytosol. M. D. Esposti, J. T. Erler, J. A. Hickman, C. Dive, Bid, a widely expressed proapoptotic protein of the Bcl-2 family, displays lipid transfer activity. Mol. Cell. Biol. 21 , 7268-7276 (2001). [Abstract] [Full Text] D. B. Ostrander, G. C. Sparagna, A. A. Amoscato, J. B. McMillihn, W. Dowhan, Decreased cardiolipin synthesis corresponds with cytochrome c release from palmitate-induced cardiomyocyte apoptosis. J. Biol. Chem. 276 , 38061-38067 (2001). [Abstract] [Full Text]