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

Abstract

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.

NME4/nucleoside diphosphate kinase D in cardiolipin signaling and mitophagy

“…15 Externalization of CL to the mitochondrial surface is also part of other damage-related signaling pathways, including early pro-apoptotic signaling [16][17][18] and inflammatory reactions in intracellular compartments and extracellular environments. 19 By providing a scaffold at the mitochondrial surface for recruiting and functionally altering different apoptotic proteins, including caspase 8, tBid, Bak, and Bax, [20][21][22] CL participates in launching the release of cytochrome c, [23][24][25][26][27][28] although this step may not be required for all forms of apoptosis. 29 In contrast to the CL that triggers mitophagy through recognition via LC3, the CL externalized during apoptosis has mostly peroxidized acyl chains, due to the CL oxidase function of cytochrome c, 30 and this oxidation step seems to be important for execution of the apoptotic program.…”

“…36 All these findings add to an emerging paradigm, namely that the myriad of different cellular lipid species, and in particular CL, have not just a supportive structural role, but are very actively involved in regulatory and signaling functions. 19,[37][38][39][40][41] …”

Association between Plasma Cellular Hypoxia and Mitochondrial Dysfunction Biomarkers and Disease Risk and Prognostic Factors in Type 2 Diabetic Saudi Patients

“…In confirmation, both of them were higher in those with lower BMI and in patients on non-insulin treatment. However, hyperglycaemia-induced myocardial apoptosis implicates CytoC release and autophagy of mitochondria (10,23). ± 68.87 mIU/L respectively; p ˂ 0.01) were significantly different.…”

“…Cytochrome c (CytoC) oxidase couples generation of adenosine triphosphate with electron transport. Leakage of CytoC signals dysfunctional mitochondria and instigates cell dismissal (10). However, CytoC activity positively correlates with autophagy, expected to maintain healthy endothelial cells (11).…”

Suitable simple and fast methods for selective isolation of phospholipids as a tool for their analysis

“…) . Among all the members of this organic compounds family, phospholipids (PLS) reveal a high scientific interest since according to their chemical nature they can be used both in pharmacological or in food applications but also have important biological activities .…”