Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Alters Mitochondrial Membrane Lipids

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to have selective antitumor activity. TRAIL induces ubiquitous pathways of cell death in which caspase activation is mediated either directly or via the release of apoptogenic factors from mitochondria; however, the precise components of the mitochondrial signaling pathway have not been well defined. Notably, mitochondria constitute an important target in overcoming resistance to TRAIL in many types of tumors. Bid is considered to be fundamental in engaging mitochondria during death receptormediated apoptosis, but this action is dependent on mitochondrial lipids. Here, we report that TRAIL signaling induces an alteration in mitochondrial membrane lipids, particularly cardiolipin. This occurs independently of caspase activation and primes mitochondrial membranes to the proapoptotic action of Bid. We unveil a link between TRAIL signaling and alteration of membrane lipid homeostasis that occurs in parallel to apical caspase activation but does not take over the mode of cell death because of the concurrent activation of caspase-8. In particular, TRAIL-induced alteration of mitochondrial lipids follows an imbalance in the cellular homeostasis of phosphatidylcholine, which results in an elevation in diacylglycerol (DAG). Elevated DAG in turn activates the D isoform of phospholipid-dependent serine/ threonine protein kinase C, which then accelerates the cleavage of caspase-8. We also show that preservation of phosphatidylcholine homeostasis by inhibition of lipiddegrading enzymes almost completely impedes the activation of pro-caspase-9 while scarcely changing the activation of caspase-8. (Cancer Res 2005; 65(18): 8286-97)

Bax activation and stress-induced apoptosis delayed by the accumulation of cholesterol in mitochondrial membranes

“…Proteins were solubilized with CHAPS, separated by size exclusion chromatography, and the elution profile of Bax was analyzed by immunoblotting. For each condition, even-numbered fractions were loaded on two separate gels; a short exposure time was chosen for the low molecular weight fractions (30-44), and a longer one for the high molecular weight fractions (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) and its sensitivity to trypsin digestion were analyzed by immunoblotting. The presence of tBid was required for the recruitment of Bax to liposomes and led to the appearance of a Tr-Bax fragment (Figure 1d).…”

“…13 Cardiolipin has often been shown to redistribute during apoptosis, and to be rapidly metabolized by oxidation and hydrolysis, which could be important for the release of mitochondrial apoptogenic factors. [14][15][16] The influence of other lipids on the process of MOM permeabilization has so far been essentially studied in vitro by looking at the permeabilization of artificial liposomes by activated Bax, 10,17 but probably because of difficulties associated with manipulating lipid levels in vivo, these studies were not pursued in cells. Moreover, an adequate Bax activation assay, allowing a reliable indication of the efficiency of its oligomerization, was missing.…”

Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response

“…The data were normalized to the major phosphatidyl choline, that is PO-PC (mass-tocharge ratio m/z 758), which was in turn normalized to other reference ions such as C-24 ceramide (m/z 685). 34 …”

Mitochondria as therapeutic targets for cancer chemotherapy

“…Of note, it appears that a growing number of MOMP-regulatory proteins are involved in lipid metabolism. This applies to phospholipid scramblase 3, carnitine palmitoyl transferase 1 (Table 1), and perhaps also t-Bid, which has been suggested to have a lipid transferase activity (Sandra et al, 2005). Mitochondria isolated from tumor cells are intrinsically resistant to the induction of MOMP, when compared to mitochondria from normal cells (Chandra et al, 2002).…”

“…Cationic ampholytes -molecules whose structure includes both a hydrophobic and a hydrophilic cationic moiety -might also be expected to preferentially redistribute to IM, not only driven by the DC m , but also because of the acidic phospholipids present in the membrane. It is important to note that the composition of mitochondrial lipids changes during apoptosis, with cardiolipin oxidation as a prominent feature (Sandra et al, 2005). This might facilitate the desorption of cyt c from IM (Ott et al, 2002).…”