Mitochondrial Lipid Alterations during Fas- and Radiation-Induced Apoptosis

Proapoptotic Bid binds to monolysocardiolipin, a new molecular connection between mitochondrial membranes and cell death

“…In liver, the dominant MCL species were identified by the peaks around m/z 1200 (Figure 4), which corresponded to salts of tri-linoleoyl (18 : 2) and di-linoleoyl, palmenyl (16 : 1) MCL, related to the predominant species of mammalian cardiolipin. 18,22 Despite the sensitivity of our MS analysis, we did not detect peaks of significant intensity that could be unambiguously assigned to DCL species (data not shown), consistent with the notion that DCL was not efficiently metabolised in isolated liver mitochondria. 22,30 The acquired capacity of analytically measured MCL was then applied to discern changes in cardiolipin homeostasis induced by apoptosis.…”

“…8,13 This observation, despite contrasting results, 15 has increased current awareness of the role of cardiolipin in the mechanism of membrane permeabilisation by proapoptotic Bcl-2 proteins. 1,16,17 However, other evidence has shown that mitochondrial cardiolipin decreases during apoptosis induced by a variety of stimuli, [18][19][20] thus creating a paradox. If Bid and Bax, which are predominantly cytosolic proteins, require cardiolipin for their action on mitochondria, 1,13,17 how can they relocate to apoptotic mitochondria, which contain reduced levels of the same lipid?…”

Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo

“…As DNR plus NOE treatment favors ceramide accumulation, it is conceivable that this lipid targets mitochondria eliciting a burst of ROS that precede mitochondrial depolarization and caspase activation. Indeed, the accumulation of ceramide in mitochondria has been reported to mediate tumor necrosis factor (TNF), Fas or radiation-induced cell death (Garcia-Ruiz et al, 1997;Matsko et al, 2001). In addition, the mitochondrial generation of ceramide upon forced expression of neutral sphingomyelinase in mitochondria leads to apoptotic cell death in MCF7 breast cancer cells (Birbes et al, 2001).…”

Chemotherapy: targeting the mitochondrial cell death pathway

“…Cationic ampholytes -molecules that contain both a hydrophobic and a hydrophilic cationic moiety -might also be expected to preferentially redistribute to IM, driven not only by the DC m , but also due to the membrane presence of acidic phospholipids. It is important to note that the composition of mitochondrial lipids changes during apoptosis, with cardiolipin oxidation as a prominent feature (Matsko et al, 2001). A local phospholipase A2 (Williams and Gottlieb, 2002) as well as a sphingomyelinase (Birbes et al, 2001) may increase the mitochondrial concentration of two potentially MMPinducing agents, namely arachidonic acid and ceramide, respectively.…”