Altered Traffic of Cardiolipin during Apoptosis: Exposure on the Cell Surface as a Trigger for "Antiphospholipid Antibodies".

Valeria Manganelli,Michele Signore,Mauro Degli Esposti,Vincenzo Mattei,Tina Garofalo,Antonella Capozzi,Roberta Misasi,Maurizio Sorice,Serena Recalchi

doi:10.1155/2015/847985

Abstract

Apoptosis has been reported to induce changes in the remodelling of membrane lipids; after death receptor engagement, specific changes of lipid composition occur not only at the plasma membrane, but also in intracellular membranes. This paper focuses on one important aspect of apoptotic changes in cellular lipids, namely, the redistribution of the mitochondria-specific phospholipid, cardiolipin (CL). CL predominantly resides in the inner mitochondrial membrane, even if the rapid remodelling of its acyl chains and the subsequent degradation occur in other membrane organelles. After death receptor stimulation, CL appears to concentrate into mitochondrial “raft-like” microdomains at contact sites between inner and outer mitochondrial membranes, leading to local oligomerization of proapoptotic proteins, including Bid. Clustering of Bid in CL-enriched contacts sites is interconnected with pathways of CL remodelling that intersect membrane traffic routes dependent upon actin. In addition, CL association with cytoskeleton protein vimentin was observed. Such novel association also indicated that CL molecules may be expressed at the cell surface following apoptotic stimuli. This observation adds a novel implication of biomedical relevance. The association of CL with vimentin at the cell surface may represent a “new” target antigen in the context of the apoptotic origin of anti-vimentin/CL autoantibodies in Antiphospholipid Syndrome.

Highlights

Changes in Phospholipid Distribution during Cell ApoptosisApoptosis or programmed cell death (PCD) constitutes a physiological phenomenon that concerns any nucleated cell but is important in multicellular organisms, where it can be paradoxically considered a vital process
Valeria Manganelli,1 Antonella Capozzi,1 Serena Recalchi,1 Michele Signore,2 Vincenzo Mattei,1,3 Tina Garofalo,1 Roberta Misasi,1 Mauro Degli Esposti,4 and Maurizio Sorice1
CL predominantly resides in the inner mitochondrial membrane, even if the rapid remodelling of its acyl chains and the subsequent degradation occur in other membrane organelles

Summary

Changes in Phospholipid Distribution during Cell Apoptosis

Apoptosis or programmed cell death (PCD) constitutes a physiological phenomenon that concerns any nucleated cell but is important in multicellular organisms, where it can be paradoxically considered a vital process. Raft-like microdomains may contribute to cell polarization, mitochondrial oxidative phosphorylation, and the release of apoptogenic factors [50,51,52] by recruitment of Bcl-2 family proteins, including truncated Bid, t-Bid, and Bax following CD95/Fas triggering [50, 51] These dynamic structures could act as a sort of signaling device and/or by a “chamber” catalyzing key critical reactions as those determining apoptotic execution pathway [52, 53]. Similar findings were obtained by Karbowski et al, who demonstrated a recruitment of Bax to lipid microdomains associated with mitochondrial fission sites during the early steps of staurosporine-induced apoptosis [55] These data supported the hypothesis that CL is an essential constituent of functional microdomains present within the contact sites between the inner and outer mitochondrial membranes [30, 56,57,58] from which it may drive the oligomerization and proapoptotic action of death inducing proteins

Cardiolipin-Bid Interaction following Apoptotic Triggering

Findings

Conclusions