Known unknowns of cardiolipin signaling: The best is yet to come

Abstract

Since its discovery 75 years ago, a wealth of knowledge has accumulated on the role of cardiolipin, the hallmark phospholipid of mitochondria, in bioenergetics and particularly on the structural organization of the inner mitochondrial membrane. A surge of interest in this anionic doubly-charged tetra-acylated lipid found in both prokaryotes and mitochondria has emerged based on its newly discovered signaling functions. Cardiolipin displays organ, tissue, cellular and transmembrane distribution asymmetries. A collapse of the membrane asymmetry represents a pro-mitophageal mechanism whereby externalized cardiolipin acts as an “eat-me” signal. Oxidation of cardiolipin's polyunsaturated acyl chains - catalyzed by cardiolipin complexes with cytochrome c. - is a pro-apoptotic signal. The messaging functions of myriads of cardiolipin species and their oxidation products are now being recognized as important intracellular and extracellular signals for innate and adaptive immune systems. This newly developing field of research exploring cardiolipin signaling is the main subject of this review.

Magic angle spinning 31P NMR spectroscopy reveals two essentially identical ionization states for the cardiolipin phosphates in phospholipid liposomes

“…More detailed analysis of cyt c/CL interactions shows that the peroxidase function of cyt c may include several levels of “loosening” of the protein structure that are translated into different re-arrangements of the protein’s hexa-coordinated heme-iron environment [36, 37]. Detailed solid state NMR studies as well as crystallographic work suggest that small scale structural changes are sufficient for the initial induction of the peroxidase competence of cyt c /CL complexes [33, 38].…”

NME4/nucleoside diphosphate kinase D in cardiolipin signaling and mitophagy

“…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] …”

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

“…There are several “suspects” for the CL redistribution in the IMM. Given the essentiality of mitochondrial depolarization and potential involvement of redox-driven mechanisms, uncoupling proteins seem to be interesting candidates [80, 81]. The inter-membrane space translocation may be particularly challenging in terms of energetic expenditures.…”

“…Indeed, subsequent detailed studies revealed that CL peroxidation, catalyzed by cytochrome c, is required for the execution of intrinsic apoptosis in mammalian cells that have oxidizable CL species [91]. Detailed analysis of mechanisms and pathways involved in CL oxidation in apoptosis has been recently discussed in several reviews [37, 81, 92–95]. Briefly, externalization of CL in damaged mitochondria strongly enhances its availability for the intermembrane space hemoprotein, cytochrome c. This encounter results in the formation of cytochrome c/CL complex in which the normally hexa-coordinated hemoprotein adopts the penta-coordinate organization allowing for the emergence of the peroxidase catalytic competence [91].…”