Elimination of the unnecessary: Intra- and extracellular signaling by anionic phospholipids

High fidelity of biological systems is frequently achieved by duplication of the essential intracellular machineries or, removal of the entire cell, which becomes unnecessary or even harmful in altered physiological environments. Carefully controlled removal of these cells, without damaging normal cells, requires precise signaling, and is critical to maintaining homeostasis. This review describes how two anionic phospholipids - phosphatidylserine (PS) and cardiolipin (CL) - residing in distinct compartments of the cell, signal removal of “the unnecessary” using several uniform principles. One of these principles is realized by collapse of inherent transmembrane asymmetry and the externalization of the signal on the outer membrane surface - mitochondria for CL and the plasma membrane for PS - to trigger mitophagy and phagocytosis, respectively. Release from damaged cells of intracellular structures with externalized CL or externalized PS triggers their elimination by phagocytosis. Another of these principles is realized by oxidation of polyunsaturated species of CL and PS. Highly specific oxidation of CL by cytochrome c serves as a signal for mitochondria-dependent apoptosis, while oxidation of externalized PS improves its effectiveness to trigger phagocytosis of effete cells.