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Mitochondrial membrane reorganisation induced by tBid during apoptosis: cardiolipin and cytochrome c redistribution analysed by single molecule spectroscopy and microscopy

Objective

One of the main control points of programmed cell death affects the release of cytochrome c and other proapoptotic factors from the mitochondria. The detailed mechanism by which cytochrome c is completely and rapidly liberated to the cytosol is not yet well understood, but it appears to involve two steps: i) redistribution of the cytochrome c stored in the mitochondrial cristae and ii) selective permeabilization of the outer mitochondrial membrane. tBid, a proapoptotic protein of the Bcl-2 family, has been recently related to the lipidic reorganization that takes place at the mitochondria during apoptosis. Addition of tBid to mitochondria induces quick morphological changes, which interconnect cristae and make cytochromec available at the outer mitochondria l membrane.

This activity seems to depend on interactions with the mitochondrial lipid cardiolipin, which, being an anchor to cytochrome c at the inner mitochondrial membrane, redistributes during apoptosis, and mediates the selective targeting of tBid to the outer mitochondrial membrane. Recently, it has been observed by epifluorescence microscopy that tBid induces the appearance of novel cardiolipin micro-domains in monolayers. Single molecule optical techniques have been applied to study raft-associated proteins and lipid mobility in vivo and in vitro.

Fluorescence correlation spectroscopy uses the temporal dimension and constitutes a powerful tool to study lipid and protein dynamics in domain-forming membranes. It is the objective of this project to characterize the formation of cardiolipin enriched domains induced by the presence of tBid in connection with the process of mitochondrial cytochrome c redistribution that occurs during apoptosis, by means of fluorescence correlation spectroscopy and microscopy in membrane model systems and mitochondria.

Call for proposal

FP6-2005-MOBILITY-5
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Coordinator

TECHNISCHE UNIVERSITAET DRESDEN
Address
Helmholtzstraße 10
Dresden
Germany