Cardiolipin asymmetry, oxidation and signaling

• Cardiolipin asymmetries.
• Reduced trans-membrane asymmetry and externalization of CLs leads to mitophagy.
• Translocation and peroxidation of CL in apoptosis.
• Molecular asymmetry of cardiolipins and their oxidation products.
• CL asymmetry as a new therapeutic target.

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.