BBA - Molecular and Cell Biology of Lipids (v.1862, #1)
Editorial Board (i).
Reviewer Acknowledgement (iii-v).
Publishers Note (vi).
Preface by Guenther Daum (1-2).
Biosynthesis, remodeling and turnover of mitochondrial cardiolipin by Michael Schlame; Miriam L. Greenberg (3-7).
Among mitochondrial lipids, cardiolipin occupies a unique place. It is the only phospholipid that is specific to mitochondria and although it is merely a minor component, accounting for 10-20% of the total phospholipid content, cardiolipin plays an important role in the molecular organization, and thus the function of the cristae. This review covers the formation of cardiolipin, a phospholipid dimer containing two phosphatidyl residues, and its assembly into mitochondrial membranes. While a large body of literature exists on this topic, the review focuses on papers that appeared in the past three years. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.
Keywords: Lipids; Metabolism; Membrane assembly; Mitochondria;
Known unknowns of cardiolipin signaling: The best is yet to come by John J. Maguire; Yulia Y. Tyurina; Dariush Mohammadyani; Aleksandr A. Kapralov; Tamil S. Anthonymuthu; Feng Qu; Andrew A. Amoscato; Louis J. Sparvero; Vladimir A. Tyurin; Joan Planas-Iglesias; Rong-Rong He; Judith Klein-Seetharaman; Hülya Bayır; Valerian E. Kagan (8-24).
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. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.
Keywords: Cardiolipin signaling; Peroxidase; Cardiolipin oxidation; Mitophagy; Innate and adaptive immunity; Apoptosis;
Cell biology, physiology and enzymology of phosphatidylserine decarboxylase by Francesca Di Bartolomeo; Ariane Wagner; Günther Daum (25-38).
Phosphatidylethanolamine is one of the most abundant phospholipids whose major amounts are formed by phosphatidylserine decarboxylases (PSD). Here we provide a comprehensive description of different types of PSDs in the different kingdoms of life. In eukaryotes, type I PSDs are mitochondrial enzymes, whereas other PSDs are localized to other cellular compartments. We describe the role of mitochondrial Psd1 proteins, their function, enzymology, biogenesis, assembly into mitochondria and their contribution to phospholipid homeostasis in much detail. We also discuss briefly the cellular physiology and the enzymology of Psd2. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.
Keywords: Phosphatidylethanolamine; Phosphatidylserine decarboxylase; Lipids; Mitochondria;
Mitochondrial fatty acid synthesis, fatty acids and mitochondrial physiology by Alexander J. Kastaniotis; Kaija J. Autio; Juha M. Kerätär; Geoffray Monteuuis; Anne M. Mäkelä; Remya R. Nair; Laura P. Pietikäinen; Antonina Shvetsova; Zhijun Chen; J. Kalervo Hiltunen (39-48).
Mitochondria and fatty acids are tightly connected to a multiplicity of cellular processes that go far beyond mitochondrial fatty acid metabolism. In line with this view, there is hardly any common metabolic disorder that is not associated with disturbed mitochondrial lipid handling. Among other aspects of mitochondrial lipid metabolism, apparently all eukaryotes are capable of carrying out de novo fatty acid synthesis (FAS) in this cellular compartment in an acyl carrier protein (ACP)-dependent manner. The dual localization of FAS in eukaryotic cells raises the questions why eukaryotes have maintained the FAS in mitochondria in addition to the “classic” cytoplasmic FAS and what the products are that cannot be substituted by delivery of fatty acids of extramitochondrial origin. The current evidence indicates that mitochondrial FAS is essential for cellular respiration and mitochondrial biogenesis. Although both β-oxidation and FAS utilize thioester chemistry, CoA acts as acyl-group carrier in the breakdown pathway whereas ACP assumes this role in the synthetic direction. This arrangement metabolically separates these two pathways running towards opposite directions and prevents futile cycling. A role of this pathway in mitochondrial metabolic sensing has recently been proposed. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.
Keywords: Fatty acid synthesis; Thioesters; Metabolic compartmentalization; Lipoic acid; Respiration; Metabolic interaction; Lipids; Pathways;
Mitochondrial acyltransferases and glycerophospholipid metabolism by Maria R. Gonzalez-Baro; Rosalind A. Coleman (49-55).
Our understanding of the synthesis and remodeling of mitochondrial phospholipids remains incomplete. Two isoforms of glycerol-3-phosphate acyltransferase (GPAT1 and 2) and two isoforms of acylglycerol-3-phosphate acyltransferase (AGPAT4 and 5) are located on the outer mitochondrial membrane, suggesting that both lysophosphatidic acid and phosphatidic acid are synthesized in situ for de novo glycerolipid biosynthesis. However, it is believed that the phosphatidic acid substrate for cardiolipin and phosphatidylethanolamine biosynthesis is produced at the endoplasmic reticulum whereas the phosphatidic acid synthesized in the mitochondria must be transferred to the endoplasmic reticulum before it undergoes additional steps to form the mature phospholipids that are trafficked back to the mitochondria. It is unclear whether mitochondrial phospholipids are remodeled by mitochondrial acyltransferases or whether lysophospholipids must return to the endoplasmic reticulum or to the mitochondrial associated membrane for reesterification. In this review we will focus on the few glycerolipid acyltransferases that are known to be mitochondrial. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.
Keywords: Glycerolipid; Remodeling; Phosphatidic acid; Acyltransferase; Mitochondrial associated membrane; Phospholipid;
Sphingolipids in mitochondria by María José Hernández-Corbacho; Mohamed F. Salama; Daniel Canals; Can E. Senkal; Lina M. Obeid (56-68).
Sphingolipids are bioactive lipids found in cell membranes that exert a critical role in signal transduction. In recent years, it has become apparent that sphingolipids participate in growth, senescence, differentiation and apoptosis. The anabolism and catabolism of sphingolipids occur in discrete subcellular locations and consist of a strictly regulated and interconnected network, with ceramide as the central hub. Altered sphingolipid metabolism is linked to several human diseases. Hence, an advanced knowledge of how and where sphingolipids are metabolized is of paramount importance in order to understand the role of sphingolipids in cellular functions. In this review, we provide an overview of sphingolipid metabolism. We focus on the distinct pathways of ceramide synthesis, highlighting the mitochondrial ceramide generation, transport of ceramide to mitochondria and its role in the regulation of mitochondrial-mediated apoptosis, mitophagy and implications to disease. We will discuss unanswered questions and exciting future directions. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.
Keywords: Sphingolipid metabolism; Ceramide; Mitochondrial apoptosis; Mitophagy; Cancer;
Mitochondrial contact sites as platforms for phospholipid exchange by Kai Stefan Dimmer; Doron Rapaport (69-80).
Mitochondria are unique organelles that contain their own – although strongly reduced – genome, and are surrounded by two membranes. While most cellular phospholipid biosynthesis takes place in the ER, mitochondria harbor the whole spectrum of glycerophospholipids common to biological membranes. Mitochondria also contribute to overall phospholipid biosynthesis in cells by producing phosphatidylethanolamine, phosphatidylglycerol, and cardiolipin. Considering these features, it is not surprising that mitochondria maintain highly active exchange of phospholipids with other cellular compartments. In this contribution we describe the transport of phospholipids between mitochondria and other organelles, and discuss recent developments in our understanding of the molecular functions of the protein complexes that mediate these processes. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.
Keywords: ERMES complex; vCLAMP; Mitochondria; Phospholipids; Contact sites;
Intramitochondrial phospholipid trafficking by Takashi Tatsuta; Thomas Langer (81-89).
Mitochondrial functions and architecture rely on a defined lipid composition of their outer and inner membranes, which are characterized by a high content of non-bilayer phospholipids such as cardiolipin (CL) and phosphatidylethanolamine (PE). Mitochondrial membrane lipids are synthesized in the endoplasmic reticulum (ER) or within mitochondria from ER-derived precursor lipids, are asymmetrically distributed within mitochondria and can relocate in response to cellular stress. Maintenance of lipid homeostasis thus requires multiple lipid transport processes to be orchestrated within mitochondria. Recent findings identified members of the Ups/PRELI family as specific lipid transfer proteins in mitochondria that shuttle phospholipids between mitochondrial membranes. They cooperate with membrane organizing proteins that preserve the spatial organization of mitochondrial membranes and the formation of membrane contact sites, unravelling an intimate crosstalk of membrane lipid transport and homeostasis with the structural organization of mitochondria.This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.
Keywords: Mitochondria; Cristae; Lipid transfer proteins; Membrane contact sites; Cardiolipin; Ups/PRELI;
Mitochondrial cholesterol import by Pia Elustondo; Laura A. Martin; Barbara Karten (90-101).
All animal subcellular membranes require cholesterol, which influences membrane fluidity and permeability, fission and fusion processes, and membrane protein function. The distribution of cholesterol among subcellular membranes is highly heterogeneous and the cholesterol content of each membrane must be carefully regulated. Compared to other subcellular membranes, mitochondrial membranes are cholesterol-poor, particularly the inner mitochondrial membrane (IMM). As a result, steroidogenesis can be controlled through the delivery of cholesterol to the IMM, where it is converted to pregnenolone. The low basal levels of cholesterol also make mitochondria sensitive to changes in cholesterol content, which can have a relatively large impact on the biophysical and functional characteristics of mitochondrial membranes. Increased mitochondrial cholesterol levels have been observed in diverse pathological conditions including cancer, steatohepatitis, Alzheimer disease and Niemann-Pick Type C1-deficiency, and are associated with increased oxidative stress, impaired oxidative phosphorylation, and changes in the susceptibility to apoptosis, among other alterations in mitochondrial function. Mitochondria are not included in the vesicular trafficking network; therefore, cholesterol transport to mitochondria is mostly achieved through the activity of lipid transfer proteins at membrane contact sites or by cytosolic, diffusible lipid transfer proteins. Here we will give an overview of the main mechanisms involved in mitochondrial cholesterol import, focusing on the steroidogenic acute regulatory protein StAR/STARD1 and other members of the StAR-related lipid transfer (START) domain protein family, and we will discuss how changes in mitochondrial cholesterol levels can arise and affect mitochondrial function. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.
Keywords: Mitochondrial cholesterol; START proteins; STARD1; STARD3; Lipid transfer proteins; Membrane contact sites;
Effects of lipids on mitochondrial functions by Christoph U. Mårtensson; Kim Nguyen Doan; Thomas Becker (102-113).
Mitochondria contain two membranes: the outer and inner membrane. Whereas the outer membrane is particularly enriched in phospholipids, the inner membrane has an unusual high protein content and forms large invaginations termed cristae. The proper phospholipid composition of the membranes is crucial for mitochondrial functions. Phospholipids affect activity, biogenesis and stability of protein complexes including protein translocases and respiratory chain supercomplexes. Negatively charged phospholipids such as cardiolipin are important for the architecture of the membranes and recruit soluble factors to the membranes to support mitochondrial dynamics. Thus, phospholipids not only form the hydrophobic core of biological membranes that surround mitochondria, but also create a specific environment to promote functions of various protein machineries. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.
Keywords: Mitochondria; Cardiolipin; Respiratory chain; Protein import; Mitochondrial dynamics;
Regulation of autophagy by mitochondrial phospholipids in health and diseases by Paul Hsu; Yuguang Shi (114-129).
Autophagy is an evolutionarily conserved mechanism that maintains nutrient homeostasis by degrading protein aggregates and damaged organelles. Autophagy is reduced in aging, which is implicated in the pathogenesis of aging-related diseases, including cancers, obesity, type 2 diabetes, cardiovascular diseases, and neurodegenerative diseases. Mitochondria-derived phospholipids cardiolipin, phosphatidylethanolamine, and phosphatidylglycerol are critical throughout the autophagic process, from initiation and phagophore formation to elongation and fusion with endolysosomal vesicles. Cardiolipin is also required for mitochondrial fusion and fission, an important step in isolating dysfunctional mitochondria for mitophagy. Furthermore, genetic screen in yeast has identified a surprising role for cardiolipin in regulating lysosomal function. Phosphatidylethanolamine plays a pivotal role in supporting the autophagic process, including autophagosome elongation as part of lipidated Atg8/LC3. An emerging role for phosphatidylglycerol in AMPK and mTORC1 signaling as well as mitochondrial fission may provide the first glimpse into the function of phosphatidylglycerol apart from being a precursor for cardiolipin. This review examines the effects of manipulating phospholipids on autophagy and mitophagy in health and diseases, as well as current limitations in the field. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.
Keywords: Autophagy; Cardiolipin; Mitophagy; Phosphatidylethanolamine; Phosphatidylglycerol;