Cardiolipin asymmetry, oxidation and signaling

Abstract

Cardiolipins (CLs) are ancient and unusual dimeric phospholipids localized in the plasma membrane of bacteria and in the inner mitochondrial membrane of eukaryotes. In mitochondria, two types of asymmetries--trans-membrane and molecular--are essential determinants of CL functions. In this review, we describe CL-based signaling mitochondrial pathways realized via modulation of trans-membrane asymmetry and leading to externalization and peroxidation of CLs in mitophagy and apoptosis, respectively. We discuss possible mechanisms of CL translocations from the inner leaflet of the inner to the outer leaflet of the outer mitochondrial membranes. We present redox reaction mechanisms of cytochrome c-catalyzed CL peroxidation as a required stage in the execution of apoptosis. We also emphasize the significance of CL-related metabolic pathways as new targets for drug discovery. Finally, a remarkable diversity of polyunsaturated CL species and their oxidation products have evolved in eukaryotes vs. prokaryotes. This diversity--associated with CL molecular asymmetry--is presented as the basis for mitochondrial communications language.

Keywords: Apoptosis; Cardiolipin; Cardiolipin asymmetry; Cardiolipin oxidation mitochondria; Mitophagy.

Figure 1

Mitophagic Translocation of Cardiolipin: Cardiolipin (CL) is synthesized by Cardiolipin Synthase (CLS) in the inner leaflet of IMM, where it can be remodeled by Tafazzin and MLCLAT, but can also translocate to OMM and ER for remodeling during its maturation. In healthy mitochondria, the large majority of CL remains at the site of its synthesis in the IMM. Externalization of cardiolipin to the mitochondrial surface through a mechanism involving phospholipid scramblase-3 (PLS3) is a prerequisite for its recognition by LC3 as a mitophagic “eat-me signal” that targets dysfunctional mitochondria to the autophagosomal machinery. While the precise mechanism of PLS3 regulation remains to be delineated, nucleoside diphosphate kinase (NDPK-D) may physically facilitate such a transfer. NDPK-D regulates the balance between di- and tri-phospho-nucleotides, providing GTP for the GTPase activity of OPA1. By forming a hexamer in the intermembrane space, NDPK-D can physically bridge the IMM and OMM. The switch from a phosphotransfer to a cardiolipin-translocating mode would thus faciliate the redistribution of cardiolipins between IMM and OMM.

Figure 2

Collapse of cardiolipin asymmetry and its redistribuition from IMM top OMM is required for the execution of both mitophagy and apoptosis. However, cardiolipin peroxidation is not necessary for mitophagy but it is a pre-requisite for the release of pro-apoptotic factors from mitochondria into the cytosol.