title: Known unknowns of cardiolipin signaling: The best is yet to come.
abstract: Since its discovery 75years 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. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors: John J
authors: JJ
authors: Maguire
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors: Yulia Y
authors: YY
authors: Tyurina
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors: Dariush
authors: D
authors: Mohammadyani
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors: Aleksandr A
authors: AA
authors: Kapralov
authors: Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors: Tamil S
authors: TS
authors: Anthonymuthu
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors: Feng
authors: F
authors: Qu
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors: Andrew A
authors: AA
authors: Amoscato
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors: Louis J
authors: LJ
authors: Sparvero
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors: Vladimir A
authors: VA
authors: Tyurin
authors: Division of Metabolic and Vascular Health, Medical School, University of Warwick, Coventry CV47AL, UK.
authors: Joan
authors: J
authors: Planas-Iglesias
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors: Rong-Rong
authors: RR
authors: He
authors: Division of Metabolic and Vascular Health, Medical School, University of Warwick, Coventry CV47AL, UK.
authors: Judith
authors: J
authors: Klein-Seetharaman
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15260, USA. Electronic address: bayihx@ccm.upmc.edu.
authors: Hülya
authors: H
authors: Bayır
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15260, USA. Electronic address: kagan@pitt.edu.
authors: Valerian E
authors: VE
authors: Kagan
mesh_terms: D000818:Animals; D002308:Cardiolipins / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D002308:Cardiolipins; D010743:Phospholipids; D045304:Cytochromes c
keywords: Apoptosis; Cardiolipin oxidation; Cardiolipin signaling; Innate and adaptive immunity; Mitophagy; Peroxidase